bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relapse severity and recovery in early pediatric multiple sclerosis
Authors: Fay Alex J , Mowry Ellen M , Strober Jonathan , Waubant Emmanuelle 
Published: December 2011

Background: Factors determining severity and recovery of early demyelinating events in pediatric multiple sclerosis (MS) patients are unknown. Objective: The objective of this study was to characterize the severity and recovery of early demyelinating events in pediatric MS. Methods: Multivariate logistic regression was performed to determine predictors of severe (versus mild/moderate) relapses and poor or fair (versus complete) recovery in patients aged 18 years or less with MS or clinically isolated syndrome (CIS). Results: Optic nerve involvement (OR 4.30, 95% CI 1.50–12.3, p = 0.007) was associated with a severe initial demyelinating event (IDE), while non-White race (OR 2.55, 95% CI 0.87–7.49, p = 0.088), localization to the cerebral hemispheres (OR 7.94, 95% CI 0.86–73.8, p = 0.068), or encephalopathy (OR 8.70, 95% CI 0.86–88.0, p = 0.067) showed a trend towards increased IDE severity. A similar association with race was found for severe second events. A severe IDE (OR 6.90, 95% CI 2.47–19.3, p < 0.001) was associated with incomplete IDE recovery, with similar trends for second and third events. Incomplete recovery from the first event predicted incomplete second event recovery (OR 3.36, 95% CI 0.98–11.6, p = 0.055). Conclusions: These results may help identify children at risk for a more aggressive disease course.
Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: ten new aquaporin-4 antibody positive cases and a review of the literature
Authors: Jarius S , Paul F , Franciotta D , de Seze J , Münch C , Salvetti M , Ruprecht K , Liebetrau M , Wandinger KP , Akman-Demir G , Melms A , Kristoferitsch W , Wildemann B 
Published: December 2011

Background: Neuromyelitis optica (NMO, Devic syndrome) and myasthenia gravis (MG) are rare antibody-mediated autoimmune disorders. Concurrent incidence has been reported in only few patients, mostly non-Caucasians. Objective: To report on ten Caucasian patients with NMO spectrum disorders (NMOSD) and MG and to provide a comprehensive review of the literature. Method: Retrospective study. Results: In total, 26 patients (m:f = 1:12; Caucasian in 12) with MG (generalized in 17) and NMOSD (NMO in 21, longitudinally extensive transverse myelitis in five) were identified from the authors’ own files ( n = 10) and the previous literature ( n = 16). MG preceded NMOSD in 24/25 cases (96%). AQP4-Ab were tested in 20 patients and were positive in 17 (85%). Twenty out of 25 patients (80%) had been treated with thymectomy or thymic irradiation, which preceded NMOSD in all cases (median latency, 12 years; range, 0.3–32). At last follow-up, complete remission of MG was reported in 15/22 (68%), and MG was well controlled with pyridostigmine in three. Co-existing autoimmune disorders or autoimmune antibodies were reported in 17 patients. Conclusion: Our study demonstrates that i) AQP4-Ab-positive NMOSD are more commonly associated with MG in Caucasians than previously thought; ii) MG precedes NMOSD in most cases, often by more than a decade; iii) NMOSD almost exclusively occur in females with juvenile or early-onset MG; and iv) MG frequently takes an unusually mild course in patients with NMOSD. A history of thymectomy could be a possible risk factor for the later development of NMOSD. We recommend testing for AQP4-Ab in MG patients presenting with atypical motor or optic symptoms.
Obstructive sleep apnea is associated with fatigue in multiple sclerosis
Authors: Kaminska M , Kimoff RJ , Benedetti A , Robinson A , Bar-Or A , Lapierre Y , Schwartzman K , Trojan DA 
Published: December 2011

Background: Multiple sclerosis (MS) patients often suffer from fatigue. Objective: We evaluated the relationship of obstructive sleep apnea (OSA) to fatigue and sleepiness in MS patients. Methods: Ambulatory MS patients without known sleep disorders and healthy controls underwent diagnostic polysomnography and a multiple sleep latency test (objective sleepiness measure). Fatigue was measured with the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI), and subjective sleepiness by Epworth Sleepiness Scale. Covariates included age, sex, body mass index, Expanded Disability Status Scale (EDSS), depression, pain, nocturia, restless legs syndrome, and medication. Results: OSA (apnea–hypopnea index ≥15) was found in 36 of 62 MS subjects and 15 of 32 controls. After adjusting for confounders, severe fatigue (FSS ≥5) and MFI-mental fatigue (>group median) were associated with OSA and respiratory-related arousals in MS, but not control subjects. Subjective and objective sleepiness were not related to OSA in either group. In a multivariate model, variables independently associated with severe fatigue in MS were severe OSA [OR 17.33, 95% CI 2.53–199.84], EDSS [OR 1.88, 95% CI 1.21–3.25], and immunomodulating treatment [OR 0.14, 95% CI 0.023–0.65]. Conclusions: OSA was frequent in MS and was associated with fatigue but not sleepiness, independent of MS-related disability and other covariates.
Chitinase 3-like 1 plasma levels are increased in patients with progressive forms of multiple sclerosis
Authors: Cantó E , Reverter F , Morcillo-Suárez C , Matesanz F , Fernández O , Izquierdo G , Vandenbroeck K , Rodríguez-Antigüedad A , Urcelay E , Arroyo R , Otaegui D , Olascoaga J , Saiz A , Navarro A , Sanchez A , Domínguez C , Caminero A , Horga A , Tintoré M , Montalban X , Comabella M 
Published: December 2011

Background: Chitinase 3-like 1 (CHI3L1) is upregulated in a wide variety of inflammatory conditions. Recent studies have pointed to a role of CHI3L1 in multiple sclerosis (MS) pathogenesis. Objective: The objective of this study was to investigate the role of plasma CHI3L1 in MS clinical course and disease activity and to evaluate the effect of interferon-beta (IFNβ) treatment on protein levels. Methods: Plasma CHI3L1 levels were determined by ELISA in 57 healthy controls (HC), 220 untreated MS patients [66 primary progressive MS patients (PPMS), 30 secondary progressive MS patients (SPMS), and 124 relapsing–remitting MS patients (RRMS), 94 during clinical remission and 30 during relapse], and 32 MS patients receiving IFNβ treatment. A polymorphism of the CHI3L1 gene, rs4950928, was genotyped in 3274 MS patients and 3483 HC. Results: Plasma CHI3L1 levels were significantly increased in patients with progressive forms of MS compared with RRMS patients and HC. CHI3L1 levels were similar between RRMS patients in relapse and remission. A trend towards decreased CHI3L1 levels was observed in IFNβ-treated patients. Allele C of rs4950928 was significantly associated with PPMS patients and with higher plasma CHI3L1 levels. Conclusions: These findings point to a role of CHI3L1 in patients with progressive forms of MS, particularly in those with PPMS.
Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival
Authors: Hamilton Ashley , Helgason G. Vignir , Schemionek Mirle , Zhang Bin , Myssina Svetlana , Allan Elaine K. , Nicolini Franck E. , Müller-Tidow Carsten , Bhatia Ravi , Brunton Valerie G. , Koschmieder Steffen , Holyoake Tessa L. 
Published: December 2011

Abstract
Recent evidence suggests chronic myeloid leukemia (CML) stem cells are insensitive to kinase inhibitors and responsible for minimal residual disease in treated patients. We investigated whether CML stem cells, in a transgenic mouse model of CML-like disease or derived from patients, are dependent on Bcr-Abl. In the transgenic model, after retransplantation, donor-derived CML stem cells in which Bcr-Abl expression had been induced and subsequently shut off were able to persist in vivo and reinitiate leukemia in secondary recipients on Bcr-Abl reexpression. Bcr-Abl knockdown in human CD34+ CML cells cultured for 12 days in physiologic growth factors achieved partial inhibition of Bcr-Abl and downstream targets p-CrkL and p-STAT5, inhibition of proliferation and colony forming cells, but no reduction of input cells. The addition of dasatinib further inhibited p-CrkL and p-STAT5, yet only reduced input cells by 50%. Complete growth factor withdrawal plus dasatinib further reduced input cells to 10%; however, the surviving fraction was enriched for primitive leukemic cells capable of growth in a long-term culture-initiating cell assay and expansion on removal of dasatinib and addition of growth factors. Together, these data suggest that CML stem cell survival is Bcr-Abl kinase independent and suggest curative approaches in CML must focus on kinase-independent mechanisms of resistance.
A mutation in the human Uncoordinated 119 gene impairs TCR signaling and is associated with CD4 lymphopenia
Authors: Gorska Magdalena M. , Alam Rafeul 
Published: December 2011

AbstractIdiopathic CD4 lymphopenia (ICL) is an immunodeficiency disorder of unclear etiology. Here we describe a heterozygous dominant-negative missense mutation (codon 22 GGC→GTC; V22G) of the signaling adaptor protein Uncoordinated 119 (Unc119) in an ICL patient. The patient is a 32-year-old female with < 300 CD4 T cells/μL and with a history of recurrent sinusitis/otitis media, frequent episodes of shingles, a widespread fungal nail infection, fungal dermatitis, oral herpetic lesions, and bronchiolitis obliterans organizing pneumonia after 2 episodes of bacterial pneumonia. The patient's cells have reduced response to TCR stimulation, with impairment in both localization and enzymatic activation of the lymphocyte-specific kinase (Lck) resulting in decreased cell proliferation. Transduction of the mutant Unc119 but not wild-type Unc119 into normal T cells reproduces the signaling and proliferation defects. The mutation disrupts the Unc119-Lck interaction which is normally needed for stimulation of the Lck catalytic activity by TCR. The mutant protein also causes mislocalization of Lck to Rab11+ perinuclear endosomes. The mutation is not present in 2 other patients with ICL, patients with secondary CD4 lymphopenia or 60 healthy subjects. The V22G mutation of Unc119 represents a novel genetic defect in ICL.
The critical role of histone H2A-deubiquitinase Mysm1 in hematopoiesis and lymphocyte differentiation
Authors: Nijnik Anastasia , Clare Simon , Hale Christine , Raisen Claire , McIntyre Rebecca E. , Yusa Kosuke , Everitt Aaron R. , Mottram Lynda , Podrini Christine , Lucas Mark , Estabel Jeanne , Goulding David ,   Sanger Institute Microarray Facility,   Sanger Mouse Genetics Project, Adams Niels , Ramirez-Solis Ramiro , White Jacqui K. , Adams David J. , Hancock Robert E. W. , Dougan Gordon 
Published: December 2011

Abstract
Stem cell differentiation and lineage specification depend on coordinated programs of gene expression, but our knowledge of the chromatin-modifying factors regulating these events remains incomplete. Ubiquitination of histone H2A (H2A-K119u) is a common chromatin modification associated with gene silencing, and controlled by the ubiquitin-ligase polycomb repressor complex 1 (PRC1) and H2A-deubiquitinating enzymes (H2A-DUBs). The roles of H2A-DUBs in mammalian development, stem cells, and hematopoiesis have not been addressed. Here we characterized an H2A-DUB targeted mouse line Mysm1tm1a/tm1a and demonstrated defects in BM hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis. Development of lymphocytes was impaired from the earliest stages of their differentiation, and there was also a depletion of erythroid cells and a defect in erythroid progenitor function. These phenotypes resulted from a cell-intrinsic requirement for Mysm1 in the BM. Importantly, Mysm1tm1a/tm1a HSCs were functionally impaired, and this was associated with elevated levels of reactive oxygen species, γH2AX DNA damage marker, and p53 protein in the hematopoietic progenitors. Overall, these data establish a role for Mysm1 in the maintenance of BM stem cell function, in the control of oxidative stress and genetic stability in hematopoietic progenitors, and in the development of lymphoid and erythroid lineages.
A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma
Authors: Zonder Jeffrey A. , Mohrbacher Ann F. , Singhal Seema , van Rhee Frits , Bensinger William I. , Ding Han , Fry John , Afar Daniel E. H. , Singhal Anil K. 
Published: December 2011

Abstract
This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow–derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.
IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing
Authors: Spadaro Francesca , Lapenta Caterina , Donati Simona , Abalsamo Laura , Barnaba Vincenzo , Belardelli Filippo , Santini Stefano M. , Ferrantini Maria 
Published: December 2011

Abstract
Cross-presentation allows antigen-presenting cells to present exogenous antigens to CD8+ T cells, playing an essential role in controlling infections and tumor development. IFN-α induces the rapid differentiation of human mono-cytes into dendritic cells, known as IFN-DCs, highly efficient in mediating cross-presentation, as well as the cross-priming of CD8+ T cells. Here, we have investigated the mechanisms underlying the cross-presentation ability of IFN-DCs by studying the intracellular sorting of soluble ovalbumin and nonstructural-3 protein of hepatitis C virus. Our results demonstrate that, independently from the route and mechanism of antigen entry, IFN-DCs are extraordinarily competent in preserving internalized proteins from early degradation and in routing antigens toward the MHC class-I processing pathway, allowing long-lasting, cross-priming capacity. In IFN-DCs, both early and recycling endosomes function as key compartments for the storage of both antigens and MHC-class I molecules and for proteasome- and transporter-associated with Ag processing–dependent auxiliary cross-presentation pathways. Because IFN-DCs closely resemble human DCs naturally occurring in vivo in response to infections and other danger signals, these findings may have important implications for the design of vaccination strategies in neoplastic or chronic infectious diseases.
MicroRNA-27a/b controls endothelial cell repulsion and angiogenesis by targeting semaphorin 6A
Authors: Urbich Carmen , Kaluza David , Frömel Timo , Knau Andrea , Bennewitz Katrin , Boon Reinier A. , Bonauer Angelika , Doebele Carmen , Boeckel Jes-Niels , Hergenreider Eduard , Zeiher Andreas M. , Kroll Jens , Fleming Ingrid , Dimmeler Stefanie 
Published: December 2011

Abstract
MicroRNAs (miRs) are small RNAs that regulate gene expression at the posttranscriptional level. miR-27 is expressed in endothelial cells, but the specific functions of miR-27b and its family member miR-27a are largely unknown. Here we demonstrate that overexpression of miR-27a and miR-27b significantly increased endothelial cell sprouting. Inhibition of both miR-27a and miR-27b impaired endothelial cell sprout formation and induced endothelial cell repulsion in vitro. In vivo, inhibition of miR-27a/b decreased the number of perfused vessels in Matrigel plugs and impaired embryonic vessel formation in zebrafish. Mechanistically, miR-27 regulated the expression of the angiogenesis inhibitor semaphorin 6A (SEMA6A) in vitro and in vivo and targeted the 3′-untranslated region of SEMA6A. Silencing of SEMA6A partially reversed the inhibition of endothelial cell sprouting and abrogated the repulsion of endothelial cells mediated by miR-27a/b inhibition, indicating that SEMA6A is a functionally relevant miR-27 downstream target regulating endothelial cell repulsion. In summary, we show that miR-27a/b promotes angiogenesis by targeting the angiogenesis inhibitor SEMA6A, which controls repulsion of neighboring endothelial cells.
Mouse NK cell–mediated rejection of bone marrow allografts exhibits patterns consistent with Ly49 subset licensing
Authors: Sun Kai , Alvarez Maite , Ames Erik , Barao Isabel , Chen Mingyi , Longo Dan L. , Redelman Doug , Murphy William J. 
Published: December 2011

AbstractNatural killer (NK) cells can mediate the rejection of bone marrow allografts and exist as subsets based on expression of inhibitory/activating receptors that can bind MHC. In vitro data have shown that NK subsets bearing Ly49 receptors for self-MHC class I have intrinsically higher effector function, supporting the hypothesis that NK cells undergo a host MHC-dependent functional education. These subsets also play a role in bone marrow cell (BMC) allograft rejection. Thus far, little in vivo evidence for this preferential licensing across mouse strains with different MHC haplotypes has been shown. We assessed the intrinsic response potential of the different Ly49+ subsets in BMC rejection by using β2-microglobulin deficient (β2m−/−) mice as donors. Using congenic and allogeneic mice as recipients and depleting the different Ly49 subsets, we found that NK subsets bearing Ly49s, which bind “self-MHC” were found to be the dominant subset responsible for β2m−/− BMC rejection. This provides in vivo evidence for host MHC class I–dependent functional education. Interestingly, all H2d strain mice regardless of background were able to resist significantly greater amounts of β2m−/−, but not wild-type BMC than H2b mice, providing evidence that the rheostat hypothesis regarding Ly49 affinities for MHC and NK-cell function impacts BMC rejection capability.
Normalization of pre-ASCT, FDG-PET imaging with second-line, non–cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma
Authors: Moskowitz Craig H. , Matasar Matt J. , Zelenetz Andrew D. , Nimer Stephen D. , Gerecitano John , Hamlin Paul , Horwitz Steven , Moskowitz Alison J. , Noy Ariela , Palomba Lia , Perales Miguel-Angel , Portlock Carol , Straus David , Maragulia Jocelyn C. , Schoder Heiko , Yahalom Joachim 
Published: December 2011

Abstract
We previously reported that remission duration < 1 year, extranodal disease, and B symptoms before salvage chemotherapy (SLT) can stratify relapsed or refractory Hodgkin lymphoma (HL) patients into favorable and unfavorable cohorts. In addition, pre-autologous stem cell transplant (ASCT) 18FDG-PET response to SLT predicts outcome. This phase 2 study uses both pre-SLT prognostic factors and post-SLT FDG-PET response in a risk-adapted approach to improve PFS after high-dose radio-chemotherapy (HDT) and ASCT. The first SLT uses 2 cycles of ICE in a standard or augmented dose (ICE/aICE), followed by restaging FDG-PET scan. Patients with a negative scan received a transplant. If the FDG-PET scan remained positive, patients received 4 biweekly doses of gemcitabine, vinorelbine, and liposomal doxorubicin. Patients without evidence of disease progression proceeded to HDT/ASCT; those with progressive disease were study failures. At a median follow-up of 51 months, EFS analyzed by intent to treat as well as for transplanted patients is 70% and 79%, respectively. Patients transplanted with negative FDG-PET, pre-HDT/ASCT after 1 or 2 SLT programs, had an EFS of > 80%, versus 28.6% for patients with a positive scan (P < .001). This prospective study provides evidence that the goal of SLT in patients with Hodgkin lymphoma should be a negative FDG-PET scan before HDT/ASCT. The study was registered at www.clinicaltrials.gov as NCT00255723.
Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD
Authors: Paats Marthe S. , Bergen Ingrid M. , Hoogsteden Henk C. , van der Eerden Menno M. , Hendriks Rudi W. 
Published: December 2011

Chronic obstructive pulmonary disease (COPD) is associated with pulmonary and systemic inflammation. Both CD4+ and CD8+ T-lymphocytes play a key role in COPD pathogenesis, but cytokine profiles in circulating T-lymphocytes have not been well characterised.Here we report the analysis of peripheral blood T-cells from 30 stable COPD patients and 10 healthy never-smokers for interferon (IFN)-γ, interleukin (IL)-4, tumour necrosis factor (TNF)-α and the T-helper 17 cytokines IL-17A, IL-17F and IL-22 by intracellular flow cytometry.We found significantly increased proportions of IFN-γ+ and TNF-α+ CD8+ T-cells in COPD patients, when compared with healthy controls. This was most evident in patients with less severe disease. In contrast, expression profiles in circulating CD4+ T-cells were similar in COPD patients and healthy controls for all cytokines tested, except for IL-17F. COPD patients with more severely reduced diffusing capacity had lower proportions of IL-17A+ CD4+ T-cells. Proportions of IL-22+ cells in the CD4+ memory T-cell population were significantly increased in active smokers, when compared with past smokers.Collectively, this comprehensive cytokine analysis of circulating T-cells in COPD patients revealed a correlation for CD8+ T-cells between Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and IFN-γ or TNF-α expression, but not for CD4+ T-cells.
Interventions to reduce antibiotic prescription for lower respiratory tract infections: Happy Audit study
Authors: Llor Carl , Cots Josep M. , López-Valcárcel Beatriz G. , Arranz Javier , García Guillermo , Ortega Jesús , Gómez Manuel , Guerra Gloria , Monedero María J. , Alcántara Juan D. , Paredes José , Hernández Silvia , Cid Marina , Pérez Carolina , Pineda Vicenta 
Published: December 2011

This before–after study aimed to evaluate the effect of two interventions on lowering the prescription of antibiotics in lower respiratory tract infections (LRTI) in Spain.General practitioners (GPs) registered all cases with LRTIs over 3-week periods before and after an intervention, in 2008 and 2009. Two types of intervention were considered: full-intervention group (FIG), consisting of discussion sessions of the results of the first registry, courses for GPs, guidelines, patient information leaflets, workshops on rapid tests and use of the C-reactive protein (CRP) test; GPs in the partial-intervention group (PIG) underwent all of the above interventions except for the workshop on rapid tests, and they did not have access to CRP. A multilevel logistic regression analysis was performed considering the prescription of an antibiotic as the dependent variable.210 physicians were assigned to FIG and 70 to PIG. In 2009, 58 new physicians were included as a control group. 5,385 LRTIs were registered. Compared with the control group, the OR of antibiotic prescription after the intervention in the PIG was 0.42 (95% CI: 0.22–0.82) and 0.22 (95% CI: 0.12–0.38) in the FIG.Intervention led to a reduction in the prescription of antibiotics, mainly when CRP testing was available.