Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.
We report a new type of multifunctional nanomaterials, FePt@Fe2O3 yolk-shell nanoparticles, that exhibit high cytotoxicity originated from the FePt yolks and strong MR contrast enhancement resulting from the Fe2O3 shells. Encouraged by the recently observed high cytotoxicity of FePt@CoS2 yolk-shell nanoparticles, we used Fe2O3 to replace CoS2 as the shells to further explore the applications of the yolk-shell nanostructures. The ultralow IC50 value (238 +/- 9 ng of Pt/mL) of FePt@Fe2O3 yolk-shell nanoparticles likely originates from the fact that the slow oxidation and release of FePt yolks increases the cytotoxicity. Moreover, compared with two commercial magnetic resonance imaging (MRI) contrast agents, MION and Sinerem, the FePt@Fe2O3 yolk-shell nanoparticle showed stronger contrast enhancement according to their apparent transverse relaxivity values (r2* = 3.462 (microg/mL)(-1) s(-1)). The bifunctional FePt@Fe2O3 yolk-shell nanoparticles may serve both as an MRI contrast agent and as a potent anticancer drug. This work indicates that these unique yolk-shell nanoparticles may ultimately lead to new designs of multifunctional nanostructures for nanomedicine.
Background and Aims: Severe acute respiratory syndrome (SARS) is a virulent viral infection that affects a number of organs and systems. This study examined if SARS may result in cardiovascular complications. Methods and Results: 121 patients (37.5 (SD13.2) years, 36% male) diagnosed to have SARS were assessed continuously for blood pressure, pulse, and temperature during their stay in hopsital. Hypotension occurred in 61 (50.4%) patients in hospital, and was found in 28.1%, 21.5%, and 14.8% of patients during the first, second, and third week, respectively. Only one patient who had transient echocardiographic evidence of impaired left ventricular systolic function required temporary inotropic support. Tachycardia was present in 87 (71.9%) patients, and was found in 62.8%, 45.4%, and 35.5% of patients from the first to third week. It occurred independent of hypotension, and could not be explained by the presence of fever. Tachycardia was also present in 38.8% of patients at follow up. Bradycardia only occurred in 18 (14.9%) patients as a transient event. Reversible cardiomegaly was reported in 13 (10.7%) patients, but without clinical evidence of heart failure. Transient atrial fibrillation was present in one patient. Corticosteroid therapy was weakly associated with tachycardia during the second (x 2 = 3.99, p = 0.046) and third week (x 2 = 6.53, p = 0.01), although it could not explain tachycardia during follow up. Conclusions: In patients with SARS, cardiovascular complications including hypotension and tachycardia were common but usually self limiting. Bradycardia and cardiomegaly were less common, while cardiac arrhythmia was rare. However, only tachycardia persisted even when corticosteroid therapy was withdrawn.
We present an improved analysis of the final data set from the QUaD experiment. Using an improved technique to remove ground contamination, we double the effective sky area and hence increase the precision of our cosmic microwave background (CMB) power spectrum measurements by ∼30% versus that previously reported. In addition, we have improved our modeling of the instrument beams and have reduced our absolute calibration uncertainty from 5% to 3.5% in temperature. The robustness of our results is confirmed through extensive jackknife tests, and by way of the agreement that we find between our two fully independent analysis pipelines. For the standard six-parameter ΛCDM model, the addition of QUaD data marginally improves the constraints on a number of cosmological parameters over those obtained from the WMAP experiment alone. The impact of QUaD data is significantly greater for a model extended to include either a running in the scalar spectral index, or a possible tensor component, or both. Adding both the QUaD data and the results from the Arcminute Cosmology Bolometer Array Receiver experiment, the uncertainty in the spectral index running is reduced by ∼25% compared to WMAP alone, while the upper limit on the tensor-to-scalar ratio is reduced from r < 0.48 to r < 0.33 (95% c.l.). This is the strongest limit on tensors to date from the CMB alone. We also use our polarization measurements to place constraints on parity-violating interactions to the surface of last scattering, constraining the energy scale of Lorentz violating interactions to < 1.5×10 −43 GeV (68% c.l.). Finally, we place a robust upper limit on the strength of the lensing B-mode signal. Assuming a single flat band power between = 200 and = 2000, we constrain the amplitude of B-modes to be < 0.57 μK 2 (95% c.l.).
In conventional diffusion tensor imaging (DTI), water diffusion distribution is described as a 2nd-order three-dimensional (3D) diffusivity tensor. It assumes that diffusion occurs in a free and unrestricted environment with a Gaussian distribution of diffusion displacement, and consequently that diffusion weighted (DW) signal decays with diffusion factor (b-value) monoexponentially. In biological tissue, complex cellular microstructures make water diffusion a highly hindered or restricted process. Non-monoexponential decays are experimentally observed in both white matter and gray matter. As a result, DTI quantitation is b-value dependent and DTI fails to fully utilize the diffusion measurements that are inherent to tissue microstructure. Diffusion kurtosis imaging (DKI) characterizes restricted diffusion and can be readily implemented on most clinical scanners. It provides a higher-order description of water diffusion process by a 2nd-order 3D diffusivity tensor as in conventional DTI together with a 4th-order 3D kurtosis tensor. Because kurtosis is a measure of the deviation of the diffusion displacement profile from a Gaussian distribution, DKI analyses quantify the degree of diffusion restriction or tissue complexity without any biophysical assumption. In this work, the theory of diffusion kurtosis and DKI including the directional kurtosis analysis is revisited. Several recent rodent DKI studies from our group are summarized, and DKI and DTI compared for their efficacy in detecting neural tissue alterations. They demonstrate that DKI offers a more comprehensive approach than DTI in describing the complex water diffusion process in vivo. By estimating both diffusivity and kurtosis, it may provide improved sensitivity and specificity in MR diffusion characterization of neural tissues.
Cell cycle withdrawal limits proliferation of adult mammalian cardiomyocytes. Therefore, the concept of stimulating myocyte mitotic divisions has dramatic implications for cardiomyocyte regeneration and hence, cardiovascular disease. Previous reports describing manipulation of cell cycle proteins have not shown induction of cardiomyocyte mitosis after birth. We now report that cyclin A2, normally silenced in the postnatal heart, induces cardiac enlargement because of cardiomyocyte hyperplasia when constitutively expressed from embryonic day 8 into adulthood. Cardiomyocyte hyperplasia during adulthood was coupled with an increase in cardiomyoctye mitosis, noted in transgenic hearts at all time points examined, particularly during postnatal development. Several stages of mitosis were observed within cardiomyocytes and correlated with the nuclear localization of cyclin A2. Magnetic resonance analysis confirmed cardiac enlargement. These results reveal a previously unrecognized critical role for cyclin A2 in mediating cardiomyocyte mitosis, a role that may significantly impact upon clinical treatment of damaged myocardium.
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