Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is a severe, typically early onset form of cystic disease that primarily involves the kidneys and biliary tract. Phenotypic ...expression and age at presentation can be quite variable
1
. The incidence of ARPKD is 1 in 20,000 live births
2
, and its pleotropic manifestations are potentially life-threatening. Optimal care requires proper surveillance to limit morbidity and mortality, knowledgeable approaches to diagnosis and treatment, and informed strategies to optimize quality of life. Clinical management therefore is ideally directed by multidisciplinary care teams consisting of perinatologists, neonatologists, nephrologists, hepatologists, geneticists, and behavioral specialists to coordinate patient care from the perinatal period to adulthood. In May 2013, an international team of 25 multidisciplinary specialists from the US, Canada, Germany, and the United Kingdom convened in Washington, DC, to review the literature published from 1990 to 2013 and to develop recommendations for diagnosis, surveillance, and clinical management. Identification of the gene
PKHD1,
and the significant advances in perinatal care, imaging, medical management, and behavioral therapies over the past decade, provide the foundational elements to define diagnostic criteria and establish clinical management guidelines as the first steps towards standardizing the clinical care for ARPKD patients. The key issues discussed included recommendations regarding perinatal interventions, diagnostic criteria, genetic testing, management of renal and biliary-associated morbidities, and behavioral assessment. The meeting was funded by the National Institutes of Health and an educational grant from the Polycystic Kidney Disease Foundation. Here we summarize the discussions and provide an updated set of diagnostic, surveillance, and management recommendations for optimizing the pediatric care of patients with ARPKD. Specialist care of ARPKD-related complications including dialysis, transplantation, and management of severe portal hypertension will be addressed in a subsequent report. Given the paucity of information regarding targeted therapies in ARPKD, this topic was not addressed in this conference.”
ABSTRACT The events recorded by ARGO-YBJ in more than five years of data collection have been analyzed to determine the diffuse gamma-ray emission in the Galactic plane at Galactic longitudes 25° < l ...< 100° and Galactic latitudes . The energy range covered by this analysis, from ∼350 GeV to ∼2 TeV, allows the connection of the region explored by Fermi with the multi-TeV measurements carried out by Milagro. Our analysis has been focused on two selected regions of the Galactic plane, i.e., 40° < l < 100° and 65° < l < 85° (the Cygnus region), where Milagro observed an excess with respect to the predictions of current models. Great care has been taken in order to mask the most intense gamma-ray sources, including the TeV counterpart of the Cygnus cocoon recently identified by ARGO-YBJ, and to remove residual contributions. The ARGO-YBJ results do not show any excess at sub-TeV energies corresponding to the excess found by Milagro, and are consistent with the predictions of the Fermi model for the diffuse Galactic emission. From the measured energy distribution we derive spectral indices and the differential flux at 1 TeV of the diffuse gamma-ray emission in the sky regions investigated.
ABSTRACT This paper reports on the measurement of the large-scale anisotropy in the distribution of cosmic-ray arrival directions using the data collected by the air shower detector ARGO-YBJ from ...2008 January to 2009 December, during the minimum of solar activity between cycles 23 and 24. In this period, more than 2 × 1011 showers were recorded with energies between ∼1 and 30 TeV. The observed two-dimensional distribution of cosmic rays is characterized by two wide regions of excess and deficit, respectively, both of relative intensity ∼10−3 with respect to a uniform flux, superimposed on smaller size structures. The harmonic analysis shows that the large-scale cosmic-ray relative intensity as a function of R.A. can be described by the first and second terms of a Fouries series. The high event statistics allow the study of the energy dependence of the anistropy, showing that the amplitude increases with energy, with a maximum intensity at ∼10 TeV, and then decreases while the phase slowly shifts toward lower values of R.A. with increasing energy. The ARGO-YBJ data provide accurate observations over more than a decade of energy around this feature of the anisotropy spectrum.
The extended TeV gamma-ray source ARGO J2031+4157 (or MGRO J2031+41) is positionally consistent with the Cygnus Cocoon discovered by Fermi-LAT at GeV energies in the Cygnus superbubble. Reanalyzing ...the ARGO-YBJ data collected from 2007 November to 2013 January, the angular extension and energy spectrum of ARGO J2031+4157 are evaluated. After subtracting the contribution of the overlapping TeV sources, the ARGO-YBJ excess map is fitted with a two-dimensional Gaussian function in a square region of 10degrees x 10degrees, finding a source extension sigma sub(ext)= 1degrees.8 + or - 0degrees.5. The observed differential energy spectrum is dN/dE = (2.5 + or - 0.4) x 10 super(-11) (E/1 TeV) super(-2.6+ or -0.3) photons cm super(-2) s super(-1) TeV super(-1), in the energy range 0.2-10 TeV. The angular extension is consistent with that of the Cygnus Cocoon as measured by Fermi-LAT and the spectrum also shows a good connection with the one measured in the 1-100 GeV energy range. These features suggest to identify ARGO J2031+4157 as the counterpart of the Cygnus Cocoon at TeV energies. The Cygnus Cocoon, located in the star-forming region of Cygnus X, is interpreted as a cocoon of freshly accelerated cosmic rays related to the Cygnus superbubble. The spectral similarity with supernova remnants (SNRs) indicates that the particle acceleration inside a superbubble is similar to that in an SNR. The spectral measurements from 1 GeV to 10 TeV allows for the first time to determine the possible spectrum slope of the underlying particle distribution. A hadronic model is adopted to explain the spectral energy distribution.
ABSTRACT We report on the extensive multi-wavelength observations of the blazar Markarian 421 (Mrk 421) covering radio to γ-rays, during the 4.5 year period of ARGO-YBJ and Fermi common operation ...time, from 2008 August to 2013 February. These long-term observations, extending over an energy range of 18 orders of magnitude, provide a unique chance to study the variable emission of Mrk 421. In particular, due to the ARGO-YBJ and Fermi data, the entire energy range from 100 MeV to 10 TeV is covered without any gap. In the observation period, Mrk 421 showed both low- and high-activity states at all wavebands. The correlations among flux variations in different wavebands were analyzed. The X-ray flux is clearly correlated with the TeV γ-ray flux, while the GeV γ-rays only show a partial correlation with the TeV γ-rays. Radio and UV fluxes seem to be weakly or not correlated with the X-ray and γ-ray fluxes. Seven large flares, including five X-ray flares and two GeV γ-ray flares with variable durations (3-58 days), and one X-ray outburst phase were identified and used to investigate the variation of the spectral energy distribution with respect to a relative quiescent phase. During the outburst phase and the seven flaring episodes, the peak energy in X-rays is observed to increase from sub-keV to a few keV. The TeV γ-ray flux increases up to 0.9-7.2 times the flux of the Crab Nebula. The behavior of GeV γ-rays is found to vary depending on the flare, a feature that leads us to classify flares into three groups according to the GeV flux variation. Finally, the one-zone synchrotron self-Compton model was adopted to describe the emission spectra. Two out of three groups can be satisfactorily described using injected electrons with a power-law spectral index around 2.2, as expected from relativistic diffuse shock acceleration, whereas the remaining group requires a harder injected spectrum. The underlying physical mechanisms responsible for different groups may be related to the acceleration process or to the environment properties.
RPR127963 demonstrates an excellent pharmacokinetic profile in several species and was found to be efficacious in the prevention of restenosis in a Yucatan mini-pig model upon oral administration of ...1–5 mg/kg. The in vitro selectivity profile and SAR of the highly optimized PDGF-R tyrosine kinase inhibitor are highlighted.
RPR127963 demonstrates an excellent pharmacokinetic profile in several species and was found to be efficacious in the prevention of restenosis in a Yucatan mini-pig model upon oral administration of 1–5 mg/kg. The in vitro selectivity profile and SAR of the highly optimized PDGF-R tyrosine kinase inhibitor are highlighted.
: We have previously shown that the RNA‐binding protein HuD binds to a regulatory element in the growth‐associated protein (GAP)‐43 mRNA and that this interaction involves its first two RNA ...recognition motifs (RRMs). In this study, we investigated the functional significance of this interaction by overexpression of human HuD protein (pcHuD) or its truncated form lacking the third RRM (pcHuD I+II) in PC12 cells. Morphological analysis revealed that pcHuD cells extended short neurites containing GAP‐43‐positive growth cones in the absence of nerve growth factor (NGF). These processes also contained tubulin and F‐actin filaments but were not stained with antibodies against neurofilament M protein. In correlation with this phenotype, pcHuD cells contained higher levels of GAP‐43 without changes in levels of other NGF‐induced proteins, such as SNAP‐25 and tau. In mRNA decay studies, HuD stabilized the GAP‐43 mRNA, whereas HuD I+II did not have any effect either on GAP‐43 mRNA stability or on the levels of GAP‐43 protein. Likewise, pcHuD I+II cells showed no spontaneous neurite outgrowth and deficient outgrowth in response to NGF. Our results indicate that HuD is sufficient to increase GAP‐43 gene expression and neurite outgrowth in the absence of NGF and that the third RRM in the protein is critical for this function.
The ARGO-YBJ air shower detector monitored the Crab Nebula gamma-ray emission from 2007 November to 2013 February. The integrated signal, consisting of ~3.3 x 10 super(5) events, reached the ...statistical significance of 21.1 standard deviations. The obtained energy spectrum in the energy range 0.3-20 TeV can be described by a power law function dN/dE = I sub(0) (E/2 TeV) super(-alpha), with a flux normalization I sub(0) = (5.2 + or - 0.2) x 10 super(-12) photons cm super(-2) s super(-1) TeV super(-1) and alpha = 2.63 + or - 0.05, corresponding to an integrated flux above 1 TeV of 1.97 x 10 super(-11) photons cm super(-2) s super(-1). The systematic error is estimated to be less than 30% for the flux normalization and 0.06 for the spectral index. Assuming a power law spectrum with an exponential cutoff dN/dE = I sub(0) (E/2 TeV) super(-alpha) exp (-E/E sub(cut)), the lower limit of the cutoff energy E sub(cut) is 12 TeV, at 90% confidence level. Our extended data set allows the study of the TeV emission over long timescales. Over five years, the light curve of the Crab Nebula in 200-day bins is compatible with a steady emission with a probability of 7.3 x 10 super(-2). A correlated analysis with Fermi-LAT data over ~4.5 yr using the light curves of the two experiments gives a Pearson correlation coefficient r = 0.56 + or - 0.22. Concerning flux variations on timescales of days, a "blind" search for flares with a duration of 1-15 days gives no excess with a significance higher than four standard deviations. The average rate measured by ARGO-YBJ during the three most powerful flares detected by Fermi-LAT is 205 + or - 91 photons day super(-1), consistent with the average value of 137 + or - 10 day super(-1).
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