This policy statement focuses on children and adolescents 5 through 18 years of age. Research suggests both benefits and risks of media use for the health of children and teenagers. Benefits include ...exposure to new ideas and knowledge acquisition, increased opportunities for social contact and support, and new opportunities to access health-promotion messages and information. Risks include negative health effects on weight and sleep; exposure to inaccurate, inappropriate, or unsafe content and contacts; and compromised privacy and confidentiality. Parents face challenges in monitoring their children's and their own media use and in serving as positive role models. In this new era, evidence regarding healthy media use does not support a one-size-fits-all approach. Parents and pediatricians can work together to develop a Family Media Use Plan (www.healthychildren.org/MediaUsePlan) that considers their children's developmental stages to individualize an appropriate balance for media time and consistent rules about media use, to mentor their children, to set boundaries for accessing content and displaying personal information, and to implement open family communication about media.
The Mass of the Black Hole in Cygnus X-1 Orosz, Jerome A; McClintock, Jeffrey E; Aufdenberg, Jason P ...
The Astrophysical journal,
12/2011, Letnik:
742, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Cygnus X-1 is a binary star system that is comprised of a black hole and a massive giant companion star in a tight orbit. Building on our accurate distance measurement reported in the preceding ...paper, we first determine the radius of the companion star, thereby constraining the scale of the binary system. To obtain a full dynamical model of the binary, we use an extensive collection of optical photometric and spectroscopic data taken from the literature. By using all of the available observational constraints, we show that the orbit is slightly eccentric (both the radial velocity and photometric data independently confirm this result) and that the companion star rotates roughly 1.4 times its pseudosynchronous value. We find a black hole mass of M = 14.8 ? 1.0 M , a companion mass of M opt = 19.2 ? 1.9 M , and the angle of inclination of the orbital plane to our line of sight of i = 27.1 ? 0.8 deg.
The prognosis is poor for children and adolescents with recurrent osteosarcoma (OS). Glycoprotein non-metastatic B (gpNMB) is a glycoprotein highly expressed in OS cells. We conducted a phase II ...study of glembatumumab vedotin (GV), a fully human IgG2 monoclonal antibody (CR011) against gpNMB conjugated to the microtubule inhibitor, monomethyl auristatin E.
Patients aged ≥12 years and <50 years with relapsed or refractory OS were eligible. GV 1.9 mg/kg/dose was administered on day 1 of each 21 day cycle. Pharmacokinetics were mandatory in patients aged <15 years. gpNMB expression was measured by immunohistochemistry. The primary end-point was disease control at 4 months and Response Evaluation Criteria in Solid Tumours response. A 2-stage design was used to determine efficacy.
Twenty-two patients were enrolled, and all were evaluable for response. Antibody–drug conjugate levels were detectable in patients, although small numbers limit comparison to adult data. The toxicities observed were similar to the previous studies with GV. The most common grade III adverse event was rash. One death from end organ failure occurred possibly related to GV. Of the 22 patients, one patient had a partial response, and two had stable disease. There was no correlation between gpNMB expression and response to GV.
GV was well tolerated in this population. Although there was some antitumour activity, the extent of disease control in stage I did not meet the level required to proceed to stage II.
NCT02487979.
•GV was well tolerated with no unexpected toxicities in AYAs with recurrent OS.•AOST1521 rapidly enrolled AYAs (median age 20 years) with recurrent OS.•Although disease control was not met, some AYAs had responses, and there may be a role for GV in OS.
The epithelial-mesenchymal transition (EMT) has been implicated in conferring stem cell properties and therapeutic resistance to cancer cells. Therefore, identification of drugs that can reprogram ...EMT may provide new therapeutic strategies. Here, we report that cells derived from claudin-low mammary tumors, a mesenchymal subtype of triple-negative breast cancer, exhibit a distinctive organoid structure with extended "spikes" in 3D matrices. Upon a miR-200 induced mesenchymal-epithelial transition (MET), the organoids switch to a smoother round morphology. Based on these observations, we developed a morphological screening method with accompanying analytical pipelines that leverage deep neural networks and nearest neighborhood classification to screen for EMT-reversing drugs. Through screening of a targeted epigenetic drug library, we identified multiple class I HDAC inhibitors and Bromodomain inhibitors that reverse EMT. These data support the use of morphological screening of mesenchymal mammary tumor organoids as a platform to identify drugs that reverse EMT.
Primary progressive apraxia of speech is a recently described neurodegenerative disorder in which patients present with an isolated apraxia of speech and show focal degeneration of superior premotor ...cortex. Little is known about how these individuals progress over time, making it difficult to provide prognostic estimates. Thirteen subjects with primary progressive apraxia of speech underwent two serial comprehensive clinical and neuroimaging evaluations 2.4 years apart median age of onset = 67 years (range: 49-76), seven females. All underwent detailed speech and language, neurological and neuropsychological assessments, and magnetic resonance imaging, diffusion tensor imaging and (18)F-fluorodeoxyglucose positron emission tomography at both baseline and follow-up. Rates of change of whole brain, ventricle, and midbrain volumes were calculated using the boundary-shift integral and atlas-based parcellation, and rates of regional grey matter atrophy were assessed using tensor-based morphometry. White matter tract degeneration was assessed on diffusion-tensor imaging at each time-point. Patterns of hypometabolism were assessed at the single subject-level. Neuroimaging findings were compared with a cohort of 20 age, gender, and scan-interval matched healthy controls. All subjects developed extrapyramidal signs. In eight subjects the apraxia of speech remained the predominant feature. In the other five there was a striking progression of symptoms that had evolved into a progressive supranuclear palsy-like syndrome; they showed a combination of severe parkinsonism, near mutism, dysphagia with choking, vertical supranuclear gaze palsy or slowing, balance difficulties with falls and urinary incontinence, and one was wheelchair bound. Rates of whole brain atrophy (1.5% per year; controls = 0.4% per year), ventricular expansion (8.0% per year; controls = 3.3% per year) and midbrain atrophy (1.5% per year; controls = 0.1% per year) were elevated (P ≤ 0.001) in all 13, compared to controls. Increased rates of brain atrophy over time were observed throughout the premotor cortex, as well as prefrontal cortex, motor cortex, basal ganglia and midbrain, while white matter tract degeneration spread into the splenium of the corpus callosum and motor cortex white matter. Hypometabolism progressed over time in almost all subjects. These findings demonstrate that some subjects with primary progressive apraxia of speech will rapidly evolve and develop a devastating progressive supranuclear palsy-like syndrome ∼ 5 years after onset, perhaps related to progressive involvement of neocortex, basal ganglia and midbrain. These findings help improve our understanding of primary progressive apraxia of speech and provide some important prognostic guidelines.
Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be ...isolated from human blood plasma using platelet β3 integrin-coated beads. Binding of apoA-IV to platelets requires activation of αIIbβ3 integrin, and the direct apoA-IV-αIIbβ3 interaction can be detected using a single-molecule Biomembrane Force Probe. We identify that aspartic acids 5 and 13 at the N-terminus of apoA-IV are required for binding to αIIbβ3 integrin, which is additionally modulated by apoA-IV C-terminus via intra-molecular interactions. ApoA-IV inhibits platelet aggregation and postprandial platelet hyperactivity. Human apoA-IV plasma levels show a circadian rhythm that negatively correlates with platelet aggregation and cardiovascular events. Thus, we identify apoA-IV as a novel ligand of αIIbβ3 integrin and an endogenous inhibitor of thrombosis, establishing a link between lipoprotein metabolism and cardiovascular diseases.
ABSTRACTIntrauterine growth retardation (IUGR) is associated with neurological deficits including cerebral palsy and cognitive and behavioral disabilities. The pathogenesis involves oxidative stress ...that leads to periventricular white matter injury with a paucity of mature oligodendrocytes and hypomyelination. The molecular mechanisms underlying this damage remain poorly understood. We used a rat model of IUGR created by bilateral ligation of the uterine artery at embryonic Day 19 that results in fetal growth retardation and oxidative stress in the developing brain. The IUGR rat pups showed significant delays in oligodendrocyte differentiation and myelination that resolved by 8 weeks. Bone morphogenetic protein 4 (BMP4), which inhibits oligodendrocyte maturation, was elevated in IUGR brains at postnatal time points and returned to near normal by adulthood. Despite the apparent recovery, behavioral deficiencies were found in 8-week-old female animals, suggesting that the early transient myelination defects have permanent effects. In support of these in vivo data, oligodendrocyte precursor cells cultured from postnatal IUGR rats retained increased BMP4 expression and impaired differentiation that was reversed with the BMP inhibitor noggin. Oxidants in oligodendrocyte cultures increased BMP expression, which decreased differentiation; however, abrogating BMP signaling with noggin in vitro and in BMP-deficient mice prevented these effects. Together, these findings suggest that IUGR results in delayed myelination through the generation of oxidative stress that leads to BMP4 upregulation.
The World Health Organization advocates task-shifting, the process of delegating clinical care functions from more specialized to less specialized health workers, as a strategy to achieve the United ...Nations Millennium Development Goals. However, there is a dearth of literature describing task shifting in sub-Saharan Africa, where services for antiretroviral therapy (ART) have scaled up rapidly in the face of generalized human resource crises. As part of ART services expansion in Lusaka, Zambia, we implemented a comprehensive task-shifting program among existing health providers and community-based workers. Training begins with didactic sessions targeting specialized skill sets. This is followed by an intensive period of practical mentorship, where providers are paired with trainers before working independently. We provide on-going quality assessment using key indicators of clinical care quality at each site. Program performance is reviewed with clinic-based staff quarterly. When problems are identified, clinic staff members design and implement specific interventions to address targeted areas. From 2005 to 2007, we trained 516 health providers in adult HIV treatment; 270 in pediatric HIV treatment; 341 in adherence counseling; 91 in a specialty nurse "triage" course, and 93 in an intensive clinical mentorship program. On-going quality assessment demonstrated improvement across clinical care quality indicators, despite rapidly growing patient volumes. Our task-shifting strategy was designed to address current health care worker needs and to sustain ART scale-up activities. While this approach has been successful, long-term solutions to the human resource crisis are also urgently needed to expand the number of providers and to slow staff migration out of the region.
In Gou et al., we reported that the black hole primary in the X-ray binary Cygnus X-1 is a near-extreme Kerr black hole with a spin parameter a sub(*) > 0.95 (3sigma). We confirm this result while ...setting a new and more stringent limit: a sub(*) > 0.983 at the 3sigma (99.7%) confidence level. The earlier work, which was based on an analysis of all three useful spectra that were then available, was possibly biased by the presence in these spectra of a relatively strong Compton power-law component: the fraction of the thermal seed photons scattered into the power law was f sub(s) = 23%-31%, while the upper limit for reliable application of the continuum-fitting method is f sub(s) <, ~ 25%. We have subsequently obtained six additional spectra of Cygnus X-1 suitable for the measurement of spin. Five of these spectra are of high quality with f sub(s) in the range 10%-19%, a regime where the continuum-fitting method has been shown to deliver reliable results. Individually, the six spectra give lower limits on the spin parameter that range from a sub(*) > 0.95 to a sub(*) > 0.98, allowing us to conservatively conclude that the spin of the black hole is a sub(*) > 0.983 (3sigma).
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