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1.
J Clin Invest ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31498148

RESUMO

Inflammatory destruction of iron-rich myelin is characteristic of multiple sclerosis (MS). Although iron is needed for oligodendrocytes to produce myelin during development, its deposition has also been linked to neurodegeneration and inflammation, including in MS. We report perivascular iron deposition in multiple sclerosis lesions that was mirrored in 72 lesions from 13 marmosets with experimental autoimmune encephalomyelitis. Iron accumulated mainly inside microglia/macrophages from 6 weeks after demyelination. Consistently, expression of transferrin receptor, the brain's main iron-influx protein, increased as lesions aged. Iron was uncorrelated with inflammation and postdated initial demyelination, suggesting that iron is not directly pathogenic. Iron homeostasis was at least partially restored in remyelinated, but not persistently demyelinated, lesions. Taken together, our results suggest that iron accumulation in the weeks after inflammatory demyelination may contribute to lesion repair rather than inflammatory demyelination per se.

2.
JAMA Neurol ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31403674

RESUMO

Importance: In multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non-gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target. Objective: To assess whether rim lesions are associated with patient disability and long-term lesion outcomes. Design, Setting, Participants: We performed 3 studies at the National Institutes of Health Clinical Center: (1) a prospective clinical/radiological cohort of 209 patients with MS (diagnosis according to the 2010 McDonald revised MS criteria, age ≥18 years, with 7-T or 3-T susceptibility-based brain MRI results) who were enrolled from January 2012 to March 2018 (of 209, 17 patients [8%] were excluded because of uninterpretable MRI scans); (2) a radiological/pathological analysis of expanding lesions featuring rims; and (3) a retrospective longitudinal radiological study assessing long-term lesion evolution in 23 patients with MS with yearly MRI scans for 10 years or more (earliest scan, 1992). Main Outcomes and Measures: (1) Identification of chronic rim lesions on 7-T or 3-T susceptibility-based brain MRI in 192 patients with MS and the association of rim counts with clinical disability (primary analysis) and brain volume changes (exploratory analysis). (2) Pathological characterization of 10 expanding lesions from an adult with progressive MS who came to autopsy after 7 years of receiving serial in vivo MRI scans. (3) Evaluation of annual lesion volume change (primary analysis) and T1 times (exploratory analysis) in 27 rim lesions vs 27 rimless lesions. Results: Of 209 participants, 104 (50%) were women and 32 (15%) were African American. One hundred seventeen patients (56%) had at least 1 rim lesion regardless of prior or ongoing treatment. Further, 84 patients (40%) had no rims (mean [SD] age, 47 [14] years), 66 (32%) had 1 to 3 rims (mean [SD] age, 47 [11] years), and 42 (20%) had 4 rims or more (mean [SD] age, 44 [11] years). Individuals with 4 rim lesions or more reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions. Whereas rimless lesions shrank over time (-3.6%/year), rim lesions were stable in size or expanded (2.2%/year; P < .001). Rim lesions had longer T1 times, suggesting more tissue destruction, than rimless lesions. On histopathological analysis, all 10 rim lesions that expanded in vivo had chronic active inflammation. Conclusions and Relevance: Chronic active lesions are common, are associated with more aggressive disease, exert ongoing tissue damage, and occur even in individuals treated with effective disease-modifying therapies. These results prompt the planning of MRI-based clinical trials aimed at treating perilesional chronic inflammation in MS.

3.
Luminescence ; 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273930

RESUMO

Dy3+ -doped CaAl12 O19 phosphors were synthesized utilizing a combustion method. Crystal structure and morphological examinations were performed respectively using X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques to identify the phase and morphology of the synthesized samples. Fourier transform infrared spectroscopy (FTIR) estimations were carried out using the KBr method. Photoluminescence properties (excitation and emission) were recorded at room temperature. CaAl12 O19 :Dy3+ phosphor showed two emission peaks respectively under a 350-nm excitation wavelength, centered at 477 nm and 573 nm. Dipole-dipole interaction via nonradiative energy shifting has been considered as the major cause of concentration quenching when Dy3+ concentration was more than 3 mol%. The CIE chromaticity coordinates positioned at (0.3185, 0.3580) for the CaAl12 O19 :0.03Dy3+ phosphor had a correlated color temperature (CCT) of 6057 K, which is situated in the cool white area. Existing results point out that the CaAl12 O19 :0.03Dy3+ phosphor could be a favorable candidate for use in white light-emitting diodes (WLEDs).

4.
Ann Neurol ; 85(6): 934-942, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30847935

RESUMO

Accumulating evidence corroborates the role of the "central vein sign" in the radiological diagnosis of multiple sclerosis (MS). Here, we report human magnetic resonance imaging (MRI) and corresponding pathological data that inflammation-dependent intracerebral remodeling of the vessel wall is directly associated with the prominence of intralesional veins on susceptibility-based MRI. In adult marmosets with experimental autoimmune encephalomyelitis, vessel-wall fibrosis was detected early in the demyelinating process, even in lesions <2 weeks old, though fibrosis was more evident after 6 weeks. Vascular remodeling consisted of both luminal enlargement and eccentric thickening of the perivascular space (fibrillar collagen type I deposition) and affected almost exclusively white matter, but not subpial cortical, lesions. The long-term effect of vessel remodeling in MS lesions is currently unknown, but it might potentially affect tissue repair. ANN NEUROL 2019;85:934-942.

5.
Neurology ; 92(11): 519-533, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30787160

RESUMO

OBJECTIVE: To summarize current and emerging imaging techniques that can be used to assess neuroprotection and repair in multiple sclerosis (MS), and to provide a consensus opinion on the potential utility of each technique in clinical trial settings. METHODS: Clinicians and scientists with expertise in the use of MRI in MS convened in Toronto, Canada, in November 2016 at a North American Imaging in Multiple Sclerosis (NAIMS) Cooperative workshop meeting. The discussion was compiled into a manuscript and circulated to all NAIMS members in attendance. Edits and feedback were incorporated until all authors were in agreement. RESULTS: A wide spectrum of imaging techniques and analysis methods in the context of specific study designs were discussed, with a focus on the utility and limitations of applying each technique to assess neuroprotection and repair. Techniques were discussed under specific themes, and included conventional imaging, magnetization transfer ratio, diffusion tensor imaging, susceptibility-weighted imaging, imaging cortical lesions, magnetic resonance spectroscopy, PET, advanced diffusion imaging, sodium imaging, multimodal techniques, imaging of special regions, statistical considerations, and study design. CONCLUSIONS: Imaging biomarkers of neuroprotection and repair are an unmet need in MS. There are a number of promising techniques with different strengths and limitations, and selection of a specific technique will depend on a number of factors, notably the question the trial seeks to answer. Ongoing collaborative efforts will enable further refinement and improved methods to image the effect of novel therapeutic agents that exert benefit in MS predominately through neuroprotective and reparative mechanisms.

6.
Brain ; 142(3): 633-646, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30715195

RESUMO

Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.

7.
Luminescence ; 34(3): 382-386, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30784183

RESUMO

An energy transfer process from Ce3+ to Tb3+ ions was successfully achieved in a Li2 SO4 -Al2 (SO4 )3 mixed-sulphate system. A wet-chemical synthesis was employed to prepare the Li2 SO4 -Al2 (SO4 )3 system by doping Ce3+ and Tb3+ ions individually as well as collectively. The phases were identified using X-ray diffraction studies. The as-prepared samples were characterized by FT-IR and photoluminescence measurements. Green-light emission was exhibited by Ce3+ , Tb3+ co-doped Li2 SO4 -Al2 (SO4 )3 system, thus, indicating its potential as a material for display devices or in the lamp industry.


Assuntos
Compostos de Alúmen/química , Cério/química , Compostos de Lítio/química , Sulfatos/química , Térbio/química , Transferência de Energia , Luz , Luminescência , Espectroscopia de Infravermelho com Transformada de Fourier
8.
J Magn Reson Imaging ; 50(3): 878-888, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30652391

RESUMO

BACKGROUND: MRI is the imaging modality of choice for diagnosis and intervention assessment in neurological disease. Its full potential has not been realized due in part to challenges in harmonizing advanced techniques across multiple sites. PURPOSE: To develop a method for the assessment of reliability and repeatability of advanced multisite-multisession neuroimaging studies and specifically to assess the reliability of an advanced MRI protocol, including multiband fMRI and diffusion tensor MRI, in a multisite setting. STUDY TYPE: Prospective. POPULATION: Twice repeated measurement of a single subject with stable relapsing-remitting multiple sclerosis (MS) at seven institutions. FIELD STRENGTH/SEQUENCE: A 3 T MRI protocol included higher spatial resolution anatomical scans, a variable flip-angle longitudinal relaxation rate constant (R1 ≡ 1/T1 ) measurement, quantitative magnetization transfer imaging, diffusion tensor imaging, and a resting-state fMRI (rsFMRI) series. ASSESSMENT: Multiple methods of assessing intrasite repeatability and intersite reliability were evaluated for imaging metrics derived from each sequence. STATISTICAL TESTS: Student's t-test, Pearson's r, and intraclass correlation coefficient (ICC) (2,1) were employed to assess repeatability and reliability. Two new statistical metrics are introduced that frame reliability and repeatability in the respective units of the measurements themselves. RESULTS: Intrasite repeatability was excellent for quantitative R1 , magnetization transfer ratio (MTR), and diffusion-weighted imaging (DWI) based metrics (r > 0.95). rsFMRI metrics were less repeatable (r = 0.8). Intersite reliability was excellent for R1 , MTR, and DWI (ICC >0.9), and moderate for rsFMRI metrics (ICC∼0.4). DATA CONCLUSION: From most reliable to least, using a new reliability metric introduced here, MTR > R1 > DWI > rsFMRI; for repeatability, MTR > DWI > R1 > rsFMRI. A graphical method for at-a-glance assessment of reliability and repeatability, effect sizes, and outlier identification in multisite-multisession neuroimaging studies is introduced. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:878-888.

9.
Neuroimage ; 184: 901-915, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30300751

RESUMO

The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. In particular, a precise delineation of lesions is hindered by a broad heterogeneity of lesion contrast, size, location, and shape. The goal of this study was to develop a fully-automatic framework - robust to variability in both image parameters and clinical condition - for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data of MS and non-MS cases. Scans of 1042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n = 30). Data spanned three contrasts (T1-, T2-, and T2∗-weighted) for a total of 1943 vol and featured large heterogeneity in terms of resolution, orientation, coverage, and clinical conditions. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. CNNs were trained independently with the Dice loss. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg (p ≤ 0.05), a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. In this study, we introduce a robust method to segment the spinal cord and intramedullary MS lesions on a variety of MRI contrasts. The proposed framework is open-source and readily available in the Spinal Cord Toolbox.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Redes Neurais (Computação) , Medula Espinal/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Variações Dependentes do Observador , Reconhecimento Automatizado de Padrão , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
10.
Bio Protoc ; 8(8)2018 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-29780855

RESUMO

In this protocol, we describe a method to visualize and map dural lymphatic vessels in-vivo using magnetic resonance imaging (MRI) and ex-vivo using histopathological techniques. While MRI protocols for routine imaging of meningeal lymphatics include contrast-enhanced T2-FLAIR and T1- weighted black-blood imaging, a more specific 3D mapping of the lymphatic system can be obtained by administering two distinct gadolinium-based MRI contrast agents on different days (gadofosveset and gadobutrol) and subsequently processing images acquired before and after administration of each type of contrast. In addition, we introduce methods for optimal immunostaining of lymphatic and blood vessel markers in human dura mater ex-vivo.

11.
Mult Scler ; 24(13): 1770-1772, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29106329

RESUMO

The North American Imaging in Multiple Sclerosis (NAIMS) Cooperative represents a network of 27 academic centers focused on accelerating the pace of magnetic resonance imaging (MRI) research in multiple sclerosis (MS) through idea exchange and collaboration. Recently, NAIMS completed its first project evaluating the feasibility of implementation and reproducibility of quantitative MRI measures derived from scanning a single MS patient using a high-resolution 3T protocol at seven sites. The results showed the feasibility of utilizing advanced quantitative MRI measures in multicenter studies and demonstrated the importance of careful standardization of scanning protocols, central image processing, and strategies to account for inter-site variability.

12.
Magn Reson Med ; 79(3): 1595-1601, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28617996

RESUMO

PURPOSE: To explore (i) the variability of upper cervical cord area (UCCA) measurements from volumetric brain 3D T1 -weighted scans related to gradient nonlinearity (GNL) and subject positioning; (ii) the effect of vendor-implemented GNL corrections; and (iii) easily applicable methods that can be used to retrospectively correct data. METHODS: A multiple sclerosis patient was scanned at seven sites using 3T MRI scanners with the same 3D T1 -weighted protocol without GNL-distortion correction. Two healthy subjects and a phantom were additionally scanned at a single site with varying table positions. The 2D and 3D vendor-implemented GNL-correction algorithms and retrospective methods based on (i) phantom data fit, (ii) normalization with C2 vertebral body diameters, and (iii) the Jacobian determinant of nonlinear registrations to a template were tested. RESULTS: Depending on the positioning of the subject, GNL introduced up to 15% variability in UCCA measurements from volumetric brain T1 -weighted scans when no distortion corrections were used. The 3D vendor-implemented correction methods and the three proposed methods reduced this variability to less than 3%. CONCLUSIONS: Our results raise awareness of the significant impact that GNL can have on quantitative UCCA studies, and point the way to prospectively and retrospectively managing GNL distortions in a variety of settings, including clinical environments. Magn Reson Med 79:1595-1601, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

13.
Ann Neurol ; 82(5): 719-728, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29024167

RESUMO

OBJECTIVE: Previous work measures spinal cord thinning in chronic progressive myelopathies, including human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Quantitative measurements of spinal cord atrophy are important in fully characterizing these and other spinal cord diseases. We aimed to investigate patterns of spinal cord atrophy and correlations with clinical markers. METHODS: Spinal cord cross-sectional area was measured in individuals (24 healthy controls [HCs], 17 asymptomatic carriers of HTLV-1 (AC), 47 HAM/TSP, 74 relapsing-remitting MS [RRMS], 17 secondary progressive MS [SPMS], and 40 primary progressive MS [PPMS]) from C1 to T10. Clinical disability scores, viral markers, and immunological parameters were obtained for patients and correlated with representative spinal cord cross-sectional area regions at the C2 to C3, C4 to C5, and T4 to T9 levels. In 2 HAM/TSP patients, spinal cord cross-sectional area was measured over 3 years. RESULTS: All spinal cord regions are thinner in HAM/TSP (56 mm2 [standard deviation, 10], 59 [10], 23 [5]) than in HC (76 [7], 83 [8], 38 [4]) and AC (71 [7], 78 [9], 36 [7]). SPMS (62 [9], 66 [9], 32 [6]) and PPMS (65 [11], 68 [10], 35 [7]) have thinner cervical cords than HC and RRMS (73 [9], 77 [10], 37 [6]). Clinical disability scores (Expanded Disability Status Scale [p = 0.009] and Instituto de Pesquisas de Cananeia [p = 0.03]) and CD8+ T-cell frequency (p = 0.04) correlate with T4 to T9 spinal cord cross-sectional area in HAM/TSP. Higher cerebrospinal fluid HTLV-1 proviral load (p = 0.01) was associated with thinner spinal cord cross-sectional area. Both HAM/TSP patients followed longitudinally showed thoracic thinning followed by cervical thinning. INTERPRETATION: Group average spinal cord cross-sectional area in HAM/TSP and progressive MS show spinal cord atrophy. We further hypothesize in HAM/TSP that is possible that neuroglial loss from a thoracic inflammatory process results in anterograde and retrograde degeneration of axons, leading to the temporal progression of thoracic to cervical atrophy described here. Ann Neurol 2017;82:719-728.


Assuntos
Atrofia/patologia , Líquido Cefalorraquidiano/virologia , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Paraparesia Espástica Tropical/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Adulto , Estudos de Casos e Controles , Líquido Cefalorraquidiano/citologia , Avaliação da Deficiência , Feminino , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Linfócitos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Paraparesia Espástica Tropical/sangue , Paraparesia Espástica Tropical/líquido cefalorraquidiano , Adulto Jovem
14.
Elife ; 62017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28971799

RESUMO

Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent. The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents. In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases.


Assuntos
Vasos Linfáticos/anatomia & histologia , Vasos Linfáticos/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Meninges/anatomia & histologia , Meninges/diagnóstico por imagem , Animais , Callithrix , Humanos
15.
Artigo em Inglês | MEDLINE | ID: mdl-28314848

RESUMO

BACKGROUND: After defibrillation of initial ventricular fibrillation (VF), it is crucial to prevent refibrillation to ensure successful resuscitation outcomes. Inability of the late Na+ current to inactivate leads to intracellular Ca2+ dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of the late Na+ current, on ventricular refibrillation. METHODS AND RESULTS: Long-duration VF was induced electrically in Langendorff-perfused rabbit hearts (n=22) and terminated with a defibrillator after 6 minutes. Fibrillating hearts were randomized into 3 groups: treatment with ranolazine, GS-967, or nontreated controls. In the treated groups, hearts were perfused with ranolazine or GS-967 at 2 minutes of VF. In control experiments, perfusion solution was supplemented with isotonic saline in lieu of a drug. Inducibility of refibrillation was assessed after initial long-duration VF by attempting to reinduce VF. Sustained refibrillation was successful in fewer ranolazine-treated (29.17%; P=0.005) or GS-967-treated (45.83%, P=0.035) hearts compared with that in nontreated control hearts (84.85%). In GS-967-treated hearts, significantly more spontaneous termination of initial long-duration VF was observed (66.67%; P=0.01). Ca2+ transient duration was reduced in ranolazine-treated hearts compared with that in controls (P=0.05) and also Ca2+ alternans (P=0.03). CONCLUSIONS: Late Na+ current inhibition during long-duration VF reduces the susceptibility to subsequent refibrillation, partially by mitigating dysregulation of intracellular Ca2+. These results suggest the potential therapeutic use of ranolazine and GS-967 and call for further testing in cardiac arrest models.


Assuntos
Canais de Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Cardioversão Elétrica/métodos , Ranolazina/farmacologia , Canais de Sódio/efeitos dos fármacos , Fibrilação Ventricular/terapia , Animais , Canais de Cálcio/metabolismo , Modelos Animais de Doenças , Parada Cardíaca/terapia , Modelos Logísticos , Piridinas/farmacologia , Coelhos , Distribuição Aleatória , Valores de Referência , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Estatísticas não Paramétricas , Triazóis/farmacologia , Fibrilação Ventricular/diagnóstico
16.
Neurology ; 88(15): 1439-1444, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28283598

RESUMO

OBJECTIVE: To assess the prevalence and the specificity of leptomeningeal enhancement (LME) on postcontrast T2-fluid-attenuated inversion recovery (FLAIR) MRI in multiple sclerosis (MS) compared to a variety of inflammatory and noninflammatory neurologic conditions assessed in 2 academic research hospitals. METHODS: On 3T postcontrast T2-FLAIR images, the presence of focal gadolinium enhancement was evaluated in the leptomeningeal compartment in 254 people with non-MS neurologic conditions or neurotropic viral infections. Based on their clinical diagnosis, patients were grouped as follows: (1) other-than-MS inflammatory neurologic diseases; (2) noninflammatory neurologic diseases; (3) human T-lymphotropic virus (HTLV)-infected; (4) HIV-infected; (5) healthy volunteers. RESULTS: LME was detected in 56/254 non-MS cases (22%) vs 74/299 (25%) of MS cases. LME was nearly 4-fold more frequent in non-MS inflammatory neurologic conditions (18/51 cases, 35%) than in noninflammatory neurologic conditions (3/38, 8%) and healthy volunteers (5/66, 8%). The highest prevalence of LME was detected in HTLV infection (17/38 cases, 45%), particularly in the setting of HTLV-associated myelopathy (14/25 cases, 56%). LME also frequently occurred in HIV infection (13/61 cases, 21%). Unlike in MS, LME is not associated with lower brain and cortical volumes in non-MS inflammatory neurologic conditions, including HTLV and HIV infection. CONCLUSIONS: Despite its relevance to MS pathogenesis and cortical pathology, LME is not specific to MS, occurring frequently in non-MS inflammatory neurologic conditions and especially in those patients with HTLV-associated myelopathy. Overall, this strengthens the notion that LME localizes inflammation-related focal disruption of the blood-meninges barrier and associated scarring.


Assuntos
Encefalite/diagnóstico por imagem , Encefalite/patologia , Gadolínio/metabolismo , Imagem por Ressonância Magnética , Meninges/diagnóstico por imagem , Adulto , Idoso , Estudos de Coortes , Estudos Transversais , Encefalite/líquido cefalorraquidiano , Feminino , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/diagnóstico por imagem , Humanos , Imagem Tridimensional , Contagem de Leucócitos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/diagnóstico por imagem , Bandas Oligoclonais/líquido cefalorraquidiano , Adulto Jovem
17.
Circ Cardiovasc Interv ; 10(3): e004172, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28258128

RESUMO

BACKGROUND: The therapeutic potential of renal denervation (RDN) for arrhythmias has not been fully explored. Detailed mechanistic evaluation is in order. The objective of the present study was to determine the antiarrhythmic potential of RDN in a postinfarct animal model and to determine whether any benefits relate to RDN-induced reduction of sympathetic effectors on the myocardium. METHODS AND RESULTS: Pigs implanted with single-chamber implantable cardioverter defibrillators to record ventricular arrhythmias (VAs) were subjected to percutaneous coronary occlusion to induce myocardial infarction. Two weeks later, a sham or real RDN treatment was performed bilaterally using the St Jude EnligHTN basket catheter. Parameters of ventricular remodeling and modulation of cardio-renal sympathetic axis were monitored for 3 weeks after myocardial infarction. Histological analysis of renal arteries yielded a mean neurofilament score of healthy nerves that was significantly lower in the real RDN group than in sham controls; damaged nerves were found only in the real RDN group. There was a 100% reduction in the rate of spontaneous VAs after real RDN and a 75% increase in the rate of spontaneous VAs after sham RDN (P=0.03). In the infarcted myocardium, presence of sympathetic nerves and tissue abundance of neuropeptide-Y, an indicator of sympathetic nerve activities, were significantly lower in the RDN group. Peak and mean sinus tachycardia rates were significantly reduced after RDN. CONCLUSIONS: RDN in the infarcted pig model leads to reduction of postinfarction VAs and myocardial sympathetic effectors. This may form the basis for a potential therapeutic role of RDN in postinfarct VAs.


Assuntos
Frequência Cardíaca , Coração/inervação , Rim/irrigação sanguínea , Infarto do Miocárdio/complicações , Miocárdio/patologia , Artéria Renal/inervação , Simpatectomia/métodos , Sistema Nervoso Simpático/cirurgia , Taquicardia Ventricular/prevenção & controle , Animais , Modelos Animais de Doenças , Feminino , Masculino , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Fator de Crescimento Neural/metabolismo , Neuropeptídeo Y/metabolismo , Sus scrofa , Sistema Nervoso Simpático/patologia , Sistema Nervoso Simpático/fisiopatologia , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/patologia , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo
18.
BMC Bioinformatics ; 18(1): 78, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28143607

RESUMO

BACKGROUND: Knockout strategies, particularly the concept of constrained minimal cut sets (cMCSs), are an important part of the arsenal of tools used in manipulating metabolic networks. Given a specific design, cMCSs can be calculated even in genome-scale networks. We would however like to find not only the optimal intervention strategy for a given design but the best possible design too. Our solution (PSOMCS) is to use particle swarm optimization (PSO) along with the direct calculation of cMCSs from the stoichiometric matrix to obtain optimal designs satisfying multiple objectives. RESULTS: To illustrate the working of PSOMCS, we apply it to a toy network. Next we show its superiority by comparing its performance against other comparable methods on a medium sized E. coli core metabolic network. PSOMCS not only finds solutions comparable to previously published results but also it is orders of magnitude faster. Finally, we use PSOMCS to predict knockouts satisfying multiple objectives in a genome-scale metabolic model of E. coli and compare it with OptKnock and RobustKnock. CONCLUSIONS: PSOMCS finds competitive knockout strategies and designs compared to other current methods and is in some cases significantly faster. It can be used in identifying knockouts which will force optimal desired behaviors in large and genome scale metabolic networks. It will be even more useful as larger metabolic models of industrially relevant organisms become available.


Assuntos
Algoritmos , Escherichia coli/genética , Genoma Bacteriano , Redes e Vias Metabólicas/genética , Escherichia coli/metabolismo , Técnicas de Inativação de Genes , Engenharia Metabólica , Modelos Biológicos , Distribuição Normal
19.
JAMA Neurol ; 74(3): 293-300, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28114441

RESUMO

Importance: Subclinical inflammatory demyelination and neurodegeneration often precede symptom onset in multiple sclerosis (MS). Objective: To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS. Design, Setting, and Participants: The Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant's risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERSMS]) comprising an individual's genetic burden and environmental exposures. The study dates were August 2012 to July 2015. Main Outcomes and Measures: Participants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography. Results: This study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P = .01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P = .008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population. Conclusions and Relevance: Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals. Trial Registration: clinicaltrials.gov Identifier: NCT01353547.


Assuntos
Saúde da Família , Esclerose Múltipla/complicações , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/genética , Doenças do Sistema Nervoso/etiologia , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Distribuição de Qui-Quadrado , Estudos de Coortes , Avaliação da Deficiência , Feminino , Humanos , Imagem Tridimensional , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Adulto Jovem
20.
Soc Neurosci ; 12(1): 50-64, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27295326

RESUMO

Maternal presence has a potent buffering effect on infant fear and stress responses in primates. We previously reported that maternal presence is not effective in buffering the endocrine stress response in infant rhesus monkeys reared by maltreating mothers. We have also reported that maltreating mothers show low maternal responsiveness and permissiveness/secure-base behavior. Although still not understood, it is possible that this maternal buffering effect is mediated, at least partially, through deactivation of amygdala response circuits when mothers are present. Here, we studied rhesus monkey infants that differed in the quality of early maternal care to investigate how this early experience modulated maternal buffering effects on behavioral responses to novelty during the weaning period. We also examined the relationship between these behavioral responses and structural connectivity in one of the underlying regulatory neural circuits: amygdala-prefrontal pathways. Our findings suggest that infant exploration in a novel situation is predicted by maternal responsiveness and structural integrity of amygdala-prefrontal white matter depending on maternal presence (positive relationships when mother is absent). These results provide evidence that maternal buffering of infant behavioral inhibition is dependent on the quality of maternal care and structural connectivity of neural pathways that are sensitive to early life stress.


Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/crescimento & desenvolvimento , Comportamento Materno/psicologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/crescimento & desenvolvimento , Estresse Psicológico/diagnóstico por imagem , Análise de Variância , Animais , Maus-Tratos Infantis/psicologia , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Macaca mulatta , Masculino , Mães , Atividade Motora , Testes Psicológicos , Distribuição Aleatória
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