Context:
Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release ...(LAR), many patients do not achieve biochemical control.
Objective:
Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly.
Design and Setting:
We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries.
Patients:
A total of 358 patients with medically naive acromegaly (GH >5 μg/L or GH nadir ≥1 μg/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging.
Interventions:
Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH ≥2.5μg/L and/or IGF-1 was above the upper limit of normal.
Main Outcome Measure:
The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 μg/L and normal IGF-1) at month 12.
Results:
Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% (P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 μg/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%).
Conclusions:
Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.
TDP-43, recently identified as a signature protein of the pathogenic inclusions in the brains cells of frontotemporal lobar degeneration patients, is a 43 kDa RNA-binding protein. It has been known ...mainly as a nuclear factor capable of repressing transcription and promoting exon exclusion. TDP-43 also forms distinct nuclear substructures linking different types of nuclear bodies. In this study, we provide the first evidence supporting TDP-43 as a neuronal activity-responsive factor in the dendrites of hippocampal neurons. In particular, TDP-43 resides in the somatodendrites mainly in the form of RNA granules colocalized with the post-synaptic protein PSD-95. These granules also contain RNAs including at least the β-actin mRNA and CaMKIIα mRNA. Furthermore, TDP-43 is localized in the dendritic processing (P) body and it behaves as a translational repressor in an in vitro assay. Related to this, repetitive stimuli by KCl greatly enhance the colocalization of TDP-43 granules with FMRP and Staufen 1, two RNA-binding proteins known to regulate mRNA transport and local translation in neurons. These data together suggest that TDP-43 is a neuronal activity-responsive factor functioning in the regulation of neuronal plasticity, the impairment of which would lead to the development of certain forms of neurodegenerative diseases including frontotemporal lobar degeneration.
Abstract Diabetes mellitus (DM) adversely affects the number and function of circulating endothelial progenitor cells (EPCs). Consequently, there is also a reduction in the repair mechanism of these ...cells, which is a critical and initiating factor in the development of diabetic vascular disease. The aim of the present study was to analyze miR expression profiles in EPCs from patients with DM and choose the most significantly regulated miR to study its possible role on EPC dysfunction and elucidate its mechanism of action. EPCs were collected from subjects with Type II DM and non-diabetic control subjects. Total RNA was harvested from EPCs, and a total of 5 candidate miRNAs were identified by microarray screening and were quantified by TaqMan real-time PCR. Lentiviral vectors expressing miR-126 and miR-126 inhibitor (anti-miR-126) were transfected into EPCs, and the EPC colony-forming capacity, proliferation activity, migratory activity, differentiation capacity, and apoptotic susceptibility were determined and Western Blotting and mRNA real-time PCR analyses were performed. To study the mechanisms, lentiviral vectors expressing Spred-1 and a short interfering RNA (siRNA) targeting Spred-1 were prepared. Five miRs were aberrantly downregulated in EPCs from DM patients. These miRs included miR-126, miR-21, miR-27a, miR-27b and miR-130a. Anti-miR-126 inhibited EPC proliferation, migration, and enhanced apoptosis. Restored miR-126 expression in EPCs from DM promoted EPC proliferation, migration, and inhibited EPC apoptosis ability. Despite this, miR-126 had no effect on EPC differentiation. miR-126 overexpression significantly downregulated Spred-1 in EPCs. The knockdown of Spred-1 expression in EPCs from DM promoted proliferation, migration, and inhibited apoptosis of the cells. The signal pathway of miR-126 effecting on EPCs is partially mediated through Ras/ERK/VEGF and PI3K/Akt/eNOS regulation. This study provides the first evidence that miR-126 is downregulated in EPCs from diabetic patients, and impairs EPCs-mediated function via its target, Spred-1, and through Ras/ERK/VEGF and PI3K/Akt/eNOS signal pathway.
Electromagnetic ion cyclotron (EMIC) waves can drive precipitation of tens of keV protons and relativistic electrons, and are a potential candidate for causing radiation belt flux dropouts. In this ...study, we quantitatively analyze three cases of EMIC‐driven precipitation, which occurred near the dusk sector observed by multiple Low‐Earth‐Orbiting (LEO) Polar Operational Environmental Satellites/Meteorological Operational satellite programme (POES/MetOp) satellites. During EMIC wave activity, the proton precipitation occurred from few tens of keV up to hundreds of keV, while the electron precipitation was mainly at relativistic energies. We compare observations of electron precipitation with calculations using quasi‐linear theory. For all cases, we consider the effects of other magnetospheric waves observed simultaneously with EMIC waves, namely, plasmaspheric hiss and magnetosonic waves, and find that the electron precipitation at MeV energies was predominantly caused by EMIC‐driven pitch angle scattering. Interestingly, each precipitation event observed by a LEO satellite extended over a limited L shell region (ΔL ~ 0.3 on average), suggesting that the pitch angle scattering caused by EMIC waves occurs only when favorable conditions are met, likely in a localized region. Furthermore, we take advantage of the LEO constellation to explore the occurrence of precipitation at different L shells and magnetic local time sectors, simultaneously with EMIC wave observations near the equator (detected by Van Allen Probes) or at the ground (measured by magnetometers). Our analysis shows that although EMIC waves drove precipitation only in a narrow ΔL, electron precipitation was triggered at various locations as identified by POES/MetOp over a rather broad region (up to ~4.4 hr MLT and ~1.4 L shells) with similar patterns between satellites.
Key Points
We show three cases of proton and relativistic electron precipitation observed simultaneously with EMIC waves
EMIC‐driven precipitation was observed by POES/MetOp satellites at different locations over a broad L‐MLT region
Each precipitation event extended over ΔL ~ 0.3 on average, showing that wave‐driven pitch angle scattering is localized
Oxygen isotope records of five stalagmites from Hulu Cave near Nanjing bear a remarkable resemblance to oxygen isotope records from Greenland ice cores, suggesting that East Asian Monsoon intensity ...changed in concert with Greenland temperature between 11,000 and 75,000 years before the present (yr. B.P.). Between 11,000 and 30,000 yr. B.P., the timing of changes in the monsoon, as established with230Th dates, generally agrees with the timing of temperature changes from the Greenland Ice Sheet Project Two (GISP2) core, which supports GISP2's chronology in this interval. Our record links North Atlantic climate with the meridional transport of heat and moisture from the warmest part of the ocean where the summer East Asian Monsoon originates.
ALS, or amyotrophic lateral sclerosis, is a progressive and fatal motor neuron disease with no effective medicine. Importantly, the majority of the ALS cases are with TDP-43 proteinopathies ...characterized with TDP-43-positive, ubiquitin-positive inclusions (UBIs) in the cytosol. However, the role of the mismetabolism of TDP-43 in the pathogenesis of ALS with TDP-43 proteinopathies is unclear. Using the conditional mouse gene targeting approach, we show that mice with inactivation of the Tardbp gene in the spinal cord motor neurons (HB9:Cre-Tardbplx/−) exhibit progressive and male-dominant development of ALS-related phenotypes including kyphosis, motor dysfunctions, muscle weakness/atrophy, motor neuron loss, and astrocytosis in the spinal cord. Significantly, ubiquitinated proteins accumulate in the TDP-43-depleted motor neurons of the spinal cords of HB9:Cre–Tardbplx/− mice with the ALS phenotypes. This study not only establishes an important role of TDP-43 in the long term survival and functioning of the mammalian spinal cord motor neurons, but also establishes that loss of TDP-43 function could be one major cause for neurodegeneration in ALS with TDP-43 proteinopathies.
Background: Most amyotrophic lateral sclerosis (ALS) cases are characterized with TDP-43(+), ubiquitin(+) inclusions in their diseased spinal cord motor neurons.
Results: Mice with targeted depletion of TDP-43 expression in the spinal cord motor neurons developed a range of ALS-like phenotypes.
Conclusion: TDP-43 is essential for the survival and functioning of mammalian spinal cord motor neurons.
Significance: Loss of TDP-43 function could be one major cause for neurodegeneration in ALS with TDP-43 proteinopathies.
We investigate the consequences of a nonzero bulk viscosity coefficient on the transverse momentum spectra, azimuthal momentum anisotropy, and multiplicity of charged hadrons produced in heavy ion ...collisions at LHC energies. The agreement between a realistic 3D hybrid simulation and the experimentally measured data considerably improves with the addition of a bulk viscosity coefficient for strongly interacting matter. This paves the way for an eventual quantitative determination of several QCD transport coefficients from the experimental heavy ion and hadron-nucleus collision programs.
TDP-43 is a DNA/RNA-binding protein with multicellular functions. As a pathosignature protein of a range of neurodegenerative diseases, TDP-43 is also the major component of the polyubiquitinated ...inclusions in the pathological cellular samples of these diseases. In normal cells, TDP-43 is processed and degraded by both autophagy and the ubiquitin-proteasome systems. We have found, by microarray hybridization and RT-PCR analyses, that the level of the mRNA encoding the major autophagy component Atg7 is decreased upon depletion of TDP-43 by RNAi knockdown. This decrease of the Atg7 mRNA level could be rescued by overexpression of an siRNA-resistant form of TDP-43, and it appears to be the result of destabilization of the Atg7 mRNA, to which TDP-43 could bind through its RNA recognition motif 1 domain. Furthermore, depletion of TDP-43 with the consequent loss of the Atg7 mRNA/ATG7 protein causes impairment of the autophagy and facilitates the accumulation of polyubiquitinated proteins as well as the autophagy/ubiquitin-proteasome system substrate p62 in the cells. These data demonstrate the function of TDP-43 as a maintenance factor of the autophagy system, and they suggest the existence of a feedback regulatory loop between TDP-43 and autophagy. A scenario in which loss of function of TDP-43 contributes to the development of TDP-43 proteinopathies is presented.
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