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[PMID]: 25893491
[Au] Autor:Paz Soldán MM; Raman MR; Gamez JD; Lohrey AK; Chen Y; Pirko I; Johnson AJ
[Ad] Address:Department of Neurology, Mayo Clinic, Rochester, Minnesota....
[Ti] Title:Correlation of Brain Atrophy, Disability, and Spinal Cord Atrophy in a Murine Model of Multiple Sclerosis.
[So] Source:J Neuroimaging;25(4):595-9, 2015 Jul.
[Is] ISSN:1552-6569
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: Disability progression in multiple sclerosis (MS) remains incompletely understood. Unlike lesional measures, central nervous system atrophy has a strong correlation with disability. Theiler's murine encephalomyelitis virus infection in SJL/J mice is an established model of progressive MS. We utilized in vivo MRI to quantify brain and spinal cord atrophy in this model and analyzed the temporal relationship between atrophy and disability. METHODS: Infected and control mice were followed for 12 months. Disability was assessed periodically using rotarod assay. Volumetric MRI datasets were acquired at 7 Tesla. Ventricular volume and C4-5 spinal cord cross-sectional area measurements were performed using Analyze 10. RESULTS: At 3 months, brain atrophy reached statistical significance (P = .005). In contrast, disability did not differ until 4 months post-infection (P = .0005). Cord atrophy reached significance by 9 months (P = 0.009). By 12 months, brain atrophy resulted in 111.8% increased ventricular volume (P = .00003), while spinal cord cross-sectional area was 25.6% reduced (P = .001) among cases. CONCLUSIONS: Our results suggest that significant brain atrophy precedes and predicts the development of disability, while spinal cord atrophy occurs late and correlates with severe disability. The observed temporal relationship establishes a framework for mechanisms of disability progression and enables further investigations of their underlying substrate.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1111/jon.12250

  2 / 187346 MEDLINE  
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[PMID]: 25963311
[Au] Autor:Kim SY; Wilson R; De Vries R; Kim HM; Holloway RG; Kieburtz K
[Ad] Address:Department of Bioethics, National Institutes of Health, Bethesda, MD, USA Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA scott.kim@nih.gov....
[Ti] Title:"It is not guaranteed that you will benefit": True but misleading?
[So] Source:Clin Trials;12(4):424-31, 2015 Aug.
[Is] ISSN:1740-7753
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: Participants of early-phase intervention trials for serious conditions provide high estimates of likelihood of benefit, even when informed consent forms do not promise such benefits. However, some technically correct, negatively stated benefits statements-such as "it is not guaranteed that you will benefit"-could play a role in raising expectations of benefit because in ordinary English usage such statements denote a likely but not a certain-to-occur event. METHODS: An experimental online survey of 584 English-speaking adults recruited online. They were randomized to receive one of two benefit statements ("not guaranteed" vs "some but very small chance"), using a hypothetical scenario of an early-phase clinical trial testing an intervention to treat amyotrophic lateral sclerosis. We assessed respondents' willingness to consider participating in the amyotrophic lateral sclerosis trial, their estimates of likelihood of benefit, and their explanations for those estimates. RESULTS: The two arms did not differ in willingness to consider participation in the amyotrophic lateral sclerosis trial. Those receiving "not guaranteed" benefit statement had higher estimates of benefit than those receiving "some but very small chance" statement (35.7% (standard deviation 20.2) vs 28.3% (standard deviation 22.0), p < 0.0001). A total of 43% of all respondents chose expressions of positive sentiment (hope and need to stay positive) as explanations of their estimates; these respondents' estimates of benefit were higher than others but similar between the two arms. The effect of benefit statements was greatest among those who chose "Those are just the facts" as the explanation for their estimate (31.0% (standard deviation 22.4%) in "not guaranteed" arm vs 18.9% (standard deviation 21.0%) in comparison arm, p = 0.008). CONCLUSION: The use of "not guaranteed" language in benefit statements, when compared to "small but very small chance" language, appeared to increase the perception of likelihood of benefit of entering an early-phase trial, especially among those who view their estimates of benefits as "facts." Such "no guarantee" benefit statements may be misleading and should not be used in informed consent forms.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1177/1740774515585120

  3 / 187346 MEDLINE  
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[PMID]: 25662914
[Au] Autor:Blazevski J; Petkovic F; Momcilovic M; Jevtic B; Mostarica Stojkovic M; Miljkovic D
[Ad] Address:Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Serbia....
[Ti] Title:Tumor necrosis factor stimulates expression of CXCL12 in astrocytes.
[So] Source:Immunobiology;220(7):845-50, 2015 Jul.
[Is] ISSN:1878-3279
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:It has been increasingly appreciated that tumor necrosis factor (TNF) performs various protective and anti-inflammatory functions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Recently, CXCL12 has been identified as a key inhibitor of leukocyte entry into the central nervous system (CNS) and as a regulator of inflammation resulting from the invasion. Here, a positive correlation between expression of TNF and CXCL12 in the CNS samples of EAE rats is presented. Also, it is shown that TNF potentiates CXCL12 expression in astrocytes. These results contribute to a view that TNF produced within the CNS plays a protective role in neuroinflammation.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1505
[Js] Journal subset:IM
[St] Status:In-Process

  4 / 187346 MEDLINE  
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[PMID]: 25788687
[Au] Autor:Sun J; Liu Y; Moreno S; Baudry M; Bi X
[Ad] Address:Basic Medical Sciences, College of Osteopathic Medicine of the Pacific and....
[Ti] Title:Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function.
[So] Source:J Neurosci;35(11):4706-18, 2015 Mar 18.
[Is] ISSN:1529-2401
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Angelman syndrome (AS) is a neurogenetic disorder caused by deficiency of maternally expressed ubiquitin-protein ligase E3A (UBE3A), an E3 ligase that targets specific proteins for proteasomal degradation. Although motor function impairment occurs in all patients with AS, very little research has been done to understand and treat it. The present study focuses on Ube3A deficiency-induced alterations in signaling through the mechanistic target of rapamycin (mTOR) pathway in the cerebellum of the AS mouse model and on potential therapeutic applications of rapamycin. Levels of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR, were increased in AS mice compared with wild-type mice; however, TSC2 inhibitory phosphorylation was also increased. Correspondingly, levels of phosphorylated/active mTOR were increased. Phosphorylation of the mTORC1 substrates S6 kinase 1 (S6K1) and S6 was elevated, whereas that of the mTORC2 substrates AKT and N-myc downstream regulated 1 was decreased, suggesting enhanced mTORC1 but inhibited mTORC2 signaling. Semi-chronic treatment of AS mice with rapamycin not only improved their motor performance but also normalized mTORC1 and mTORC2 signaling. Furthermore, inhibitory phosphorylation of rictor, a key regulatory/structural subunit of the mTORC2 complex, was increased in AS mice and decreased after rapamycin treatment. These results indicate that Ube3A deficiency leads to overactivation of the mTORC1-S6K1 pathway, which in turn inhibits rictor, resulting in decreased mTORC2 signaling in Purkinje neurons of AS mice. Finally, rapamycin treatment also improved dendritic spine morphology in AS mice, through inhibiting mTORC1 and possibly enhancing mTORC2-mediated regulation of synaptic cytoskeletal elements. Collectively, our results indicate that the imbalance between mTORC1 and mTORC2 activity may contribute to synaptic pathology and motor impairment in AS.
[Mh] MeSH terms primary: Angelman Syndrome/metabolism
Cerebellum/metabolism
Motor Skills/physiology
Multiprotein Complexes/metabolism
TOR Serine-Threonine Kinases/metabolism
[Mh] MeSH terms secundary: Angelman Syndrome/pathology
Animals
Cerebellum/pathology
Male
Mice
Mice, Transgenic
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Multiprotein Complexes); 0 (TOR complex 2); 0 (mechanistic target of rapamycin complex 1); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Entry month:1506
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[Da] Date of entry for processing:150319
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.4276-14.2015

  5 / 187346 MEDLINE  
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[PMID]: 25445455
[Au] Autor:Hardcastle SA; Dieppe P; Gregson CL; Arden NK; Spector TD; Hart DJ; Edwards MH; Dennison EM; Cooper C; Sayers A; Williams M; Davey Smith G; Tobias JH
[Ad] Address:Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, UK; MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, UK. Electronic address: Sarah.Hardcastle@bristol.ac.uk....
[Ti] Title:Individuals with high bone mass have an increased prevalence of radiographic knee osteoarthritis.
[So] Source:Bone;71:171-9, 2015 Feb.
[Is] ISSN:1873-2763
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:We previously reported an association between high bone mass (HBM) and a bone-forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip. HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren-Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM-OA association, using Stata v12. 609 HBM knees in 311 cases (mean age 60.8years, 74% female) and 1937 control knees in 991 controls (63.4years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren-Lawrence grade≥2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p<0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%. Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1412
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[St] Status:In-Process

  6 / 187346 MEDLINE  
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[PMID]: 26109642
[Au] Autor:Ayano M; Tsukamoto H; Kohno K; Ueda N; Tanaka A; Mitoma H; Akahoshi M; Arinobu Y; Niiro H; Horiuchi T; Akashi K
[Ad] Address:Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan;...
[Ti] Title:Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis.
[So] Source:J Immunol;195(3):892-900, 2015 Aug 1.
[Is] ISSN:1550-6606
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8(+) T cells can be detected in peripheral blood and lungs of SSc patients, effector memory CD8(+) T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8(+) T cells remain incompletely understood. In this study, we performed DNA microarray analysis of the sort-purified effector memory CD8(+) T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1 [DNAM-1]), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226(high)CD8(+) T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Furthermore, CD226(+)CD8(+) T cells produced higher amount of various cytokines than CD226(-) ones, and CD226(high)CD8(+) T cells from SSc patients showed upregulated IL-13 production and positive correlation with the cytotoxic capacity of CD8(+) T cells against HUVECs. Finally, the neutralization of CD226 in CD8(+) T cells impaired costimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8(+) T cells reflects disease severity and is involved in SSc pathogenesis via the production of various cytokines, including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Js] Journal subset:AIM; IM
[St] Status:In-Data-Review
[do] DOI:10.4049/jimmunol.1403046

  7 / 187346 MEDLINE  
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[PMID]: 26071562
[Au] Autor:Dhaeze T; Peelen E; Hombrouck A; Peeters L; Van Wijmeersch B; Lemkens N; Lemkens P; Somers V; Lucas S; Broux B; Stinissen P; Hellings N
[Ad] Address:Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; School of Life Sciences, Transnational University Limburg, 3590 Diepenbeek, Belgium;...
[Ti] Title:Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis.
[So] Source:J Immunol;195(3):832-40, 2015 Aug 1.
[Is] ISSN:1550-6606
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Follicular regulatory T cells (TFR) have been extensively characterized in mice and participate in germinal center responses by regulating the maturation of B cells and production of (auto)antibodies. We report that circulating TFR are phenotypically distinct from tonsil-derived TFR in humans. They have a lower expression of follicular markers, and display a memory phenotype and lack of high expression of B cell lymphoma 6 and ICOS. However, the suppressive function, expression of regulatory markers, and FOXP3 methylation status of blood TFR is comparable with tonsil-derived TFR. Moreover, we show that circulating TFR frequencies increase after influenza vaccination and correlate with anti-flu Ab responses, indicating a fully functional population. Multiple sclerosis (MS) was used as a model for autoimmune disease to investigate alterations in circulating TFR. MS patients had a significantly lower frequency of circulating TFR compared with healthy control subjects. Furthermore, the circulating TFR compartment of MS patients displayed an increased proportion of Th17-like TFR. Finally, TFR of MS patients had a strongly reduced suppressive function compared with healthy control subjects. We conclude that circulating TFR are a circulating memory population derived from lymphoid resident TFR, making them a valid alternative to investigate alterations in germinal center responses in the context of autoimmune diseases, and TFR impairment is prominent in MS.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Js] Journal subset:AIM; IM
[St] Status:In-Data-Review
[do] DOI:10.4049/jimmunol.1500759

  8 / 187346 MEDLINE  
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[PMID]: 26186194
[Au] Autor:Huttlin EL; Ting L; Bruckner RJ; Gebreab F; Gygi MP; Szpyt J; Tam S; Zarraga G; Colby G; Baltier K; Dong R; Guarani V; Vaites LP; Ordureau A; Rad R; Erickson BK; Wühr M; Chick J; Zhai B; Kolippakkam D; Mintseris J; Obar RA; Harris T; Artavanis-Tsakonas S; Sowa ME; De Camilli P; Paulo JA; Harper JW; Gygi SP
[Ad] Address:Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA....
[Ti] Title:The BioPlex Network: A Systematic Exploration of the Human Interactome.
[So] Source:Cell;162(2):425-40, 2015 Jul 16.
[Is] ISSN:1097-4172
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Protein interactions form a network whose structure drives cellular function and whose organization informs biological inquiry. Using high-throughput affinity-purification mass spectrometry, we identify interacting partners for 2,594 human proteins in HEK293T cells. The resulting network (BioPlex) contains 23,744 interactions among 7,668 proteins with 86% previously undocumented. BioPlex accurately depicts known complexes, attaining 80%-100% coverage for most CORUM complexes. The network readily subdivides into communities that correspond to complexes or clusters of functionally related proteins. More generally, network architecture reflects cellular localization, biological process, and molecular function, enabling functional characterization of thousands of proteins. Network structure also reveals associations among thousands of protein domains, suggesting a basis for examining structurally related proteins. Finally, BioPlex, in combination with other approaches, can be used to reveal interactions of biological or clinical significance. For example, mutations in the membrane protein VAPB implicated in familial amyotrophic lateral sclerosis perturb a defined community of interactors.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Js] Journal subset:IM
[St] Status:In-Data-Review

  9 / 187346 MEDLINE  
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[PMID]: 26089325
[Au] Autor:D'Alton S; Altshuler M; Lewis J
[Ad] Address:Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida 32610, USA.
[Ti] Title:Studies of alternative isoforms provide insight into TDP-43 autoregulation and pathogenesis.
[So] Source:RNA;21(8):1419-32, 2015 Aug.
[Is] ISSN:1469-9001
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:TDP-43 is a soluble, nuclear protein that undergoes cytoplasmic redistribution and aggregation in the majority of cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 autoregulates the abundance of its own transcript TARDBP by binding to an intron in the 3' untranslated region, although the mechanisms underlying this activity have been debated. Herein, we provide the most extensive analysis of TARDBP transcript yet undertaken. We detail the existence of a plethora of complex splicing events and alternative poly(A) use and provide data that explain the discrepancies reported to date regarding the autoregulatory capacity of TDP-43. Additionally, although many splice isoforms emanating from the TARDBP locus contain the regulated intron in the 3' UTR, we find only evidence for autoregulation of the transcript encoding full-length TDP-43. Finally, we use a novel cytoplasmic isoform of TDP to induce disease-like loss of soluble, nuclear TDP-43, which results in aberrant splicing and up-regulation of endogenous TARDBP. These results reveal a previously underappreciated complexity to TDP-43 regulated splicing and suggest that loss of TDP-43 autoregulatory capacity may contribute to the pathogenesis of ALS.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1261/rna.047647.114

  10 / 187346 MEDLINE  
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[PMID]: 26185425
[Au] Autor:Weller I; Saake A; Schreiner T; Vogelreuter J; Petroff N
[Ad] Address:Bayer Vital GmbH, Leverkusen, Germany....
[Ti] Title:Patient satisfaction with the BETACONNECTâ„¢ autoinjector for interferon beta-1b.
[So] Source:Patient Prefer Adherence;9:951-9, 2015.
[Is] ISSN:1177-889X
[Cp] Country of publication:New Zealand
[La] Language:eng
[Ab] Abstract:PURPOSE: Multiple sclerosis (MS) is a chronic demyelinating, degenerative disease requiring long-term treatment. Patient adherence to treatment may be challenging in such scenarios, especially since treatment often involves self-injection, for example, with interferon beta-1b during therapy. BETACONNECTâ„¢ is a novel electronic autoinjector for patient support in interferon beta-1b administration. The purpose of this survey was to assess patient satisfaction with the BETACONNECTâ„¢ device and its features. PATIENTS AND METHODS: A total of 2,299 MS patients using the BETACONNECTâ„¢ device were asked to participate in a survey in October 2014. All of these candidates participated in the BETAPLUS(®) program and had provided written informed consent. The participants were asked to answer 13 device-related questions. RESULTS: Of these candidates, 1,365 replied to the questionnaire, with more than 60% of the participants being 40-59 years of age. Among them, 69% were women and 21% were men (10% not specified). Approximately half of the participants received treatment with interferon beta-1b for more than 5 years. Most participants (85%) had used self-injection devices before, with 59% previously using BETACOMFORT(®), 23% using BETAJECT(®) Comfort, and 3% using BETAJECT(®) Lite, while less than 4% manually injected interferon beta-1b. The majority of the participants had received the BETACONNECTâ„¢ device from a BETAPLUS(®) nurse (87%) and 48% had already used the device for more than 2 months (49% for 2 months or less). Among the participants, more than 90% evaluated the BETACONNECTâ„¢ device as "very helpful" or "helpful" in supporting their interferon beta-1b therapy with only marginal sex differences. Features that were rated "very important" by more than half of the participants included adjustability of injection speed and depth, contact sensor for avoidance of unintentional release, optical and acoustic signals, and rechargeable battery. CONCLUSION: The vast majority of patients rated the BETACONNECTâ„¢ device as very helpful or helpful for their treatment with interferon beta-1b, and many considered most features as "very important". In conclusion, usage of the BETACONNECTâ„¢ autoinjector may facilitate interferon beta-1b therapy and support adherence to long-term therapeutic regimen.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Da] Date of entry for processing:150718
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.2147/PPA.S85917


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