Safety of gadolinium‐based contrast material in sickle cell disease

Purpose: To assess the safety of intravenously administered gadolinium‐based contrast material in sickle cell disease (SCD) patients. Materials and Methods: All pediatric and adult SCD patients evaluated by magnetic resonance imaging (MRI) at our institution between January 1995 and July 2009 were identified. The medical records of SCD patients who underwent contrast‐enhanced MRI as well as an equal‐sized cohort of SCD patients who underwent unenhanced MRI were reviewed for adverse (vaso‐occlusive and hemolytic) events within 1 week following imaging. Results: Eight (five mild and three moderate) adverse events were documented within 1 week following contrast‐enhanced MRI (38 patients and 61 contrast injections), while six (five mild and one moderate) similar events occurred within 1 week following unenhanced MRI (61 patients and 61 unenhanced MRI examinations). This difference in the number of adverse events was not statistically significant (odds ratio = 1.4; 95% confidence interval [CI] 0.4, 5.2). No severe adverse event occurred in either patient cohort. Conclusion: Gadolinium‐based contrast materials do not appear to be associated with increased risk of vaso‐occlusive or hemolytic adverse events when administered to SCD patients. Larger, prospective studies using multiple gadolinium‐based contrast materials would be useful to confirm the results of our investigation. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87070/1/22666_ftp.pd

Systematic evaluation of an atomic clock at 2e-18 total uncertainty

The pursuit of better atomic clocks has advanced many research areas, providing better quantum state control, new insights in quantum science, tighter limits on fundamental constant variation, and improved tests of relativity. The record for the best stability and accuracy is currently held by optical lattice clocks. This work takes an important step towards realizing the full potential of a many-particle clock with a state-of-the-art stable laser. Our 87Sr optical lattice clock now achieves fractional stability of 2.2e-16 at 1 s. With this improved stability, we perform a new accuracy evaluation of our clock, reducing many systematic uncertainties that limited our previous measurements, such as those in the lattice ac Stark shift, the atoms' thermal environment, and the atomic response to room-temperature BBR. Our combined measurements have reduced the total uncertainty of the JILA Sr clock to 2.1e-18 in fractional frequency units.Comment: Full published versio

Charge Ordering and Phase Competition in the Layered Perovskite Lasr2mn2o7

Charge-lattice fluctuations are observed in the layered perovskite manganite LaSr2Mn2O7 by Raman spectroscopy as high as 340 K and with decreasing temperature they become static and form a charge ordered (CO) phase below TCO=210 K. In the static regime, superlattice reflections are observed through neutron and x-ray diffraction with a propagation vector (h+1/4,k-1/4,l). Crystallographic analysis of the CO state demonstrates that the degree of charge and orbital ordering in this manganite is weaker than the charge ordering in three dimensional perovskite manganites. A TN=170K a type-A antiferromagnetism (AF) develops and competes with the charge ordering, that eventually melts below T*=100K. High resolution diffraction measurements suggest that that CO- and AF-states do not coincide within the same region in the material but rather co-exist as separate phases. The transition to type-A antiferromagnetism at lower temperatures is characterized by the competition between these two phases.Comment: 9 pages, 6 figure

Increased prevalence of potential right-to-left shunting in children with sickle cell anaemia and stroke

'Paradoxical' embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in sickle cell anaemia (SCA), predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke (SCA + stroke) have an increased prevalence of potential RLS. We performed contrasted transthoracic echocardiograms on 147 children (aged 2-19 years) with SCA + stroke) mean age 12·7 ± 4·8 years, 54·4% male) and a control group without SCA or stroke (n = 123; mean age 12·1 ± 4·9 years, 53·3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA+stroke group than controls (45·6% vs. 23·6%, P < 0·001). The odds ratio for potential RLS in the SCA + stroke group was 2·7 (95% confidence interval: 1·6-4·6) vs controls. In post hoc analyses, the SCA + stroke group had a higher prevalence of intrapulmonary (23·8% vs. 5·7%, P < 0·001) but not intracardiac shunting (21·8% vs. 18·7%, P = 0·533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent and potentially modifiable risk factor for stroke in SCA

End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain

To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points

Lattice Displacements Above Tc in the Layered Manganite La1.2Sr1.8Mn2O7

Neutron diffraction data presented in this paper demonstrates the relevance of lattice displacement above TC, in our understanding of the evolution of the crystal structure with temperature in the layered CMR manganite La1.2Sr1.8Mn2O7. The anomalous temperature behavior of thermal diffuse scattering (TDS) in La1.2Sr1.8Mn2O7 strongly suggests that it arises from lattice displacements and correlates directly with anomalies in the displacement parameters of the O- and Mn-atoms and Mn-O bond lengths. From our measurements, the insulator - metal transition can be described as a transition from a high temperature state with disordered Mn-O bond lengths to a low temperature state with a more uniform distribution on Mn-O bonds. These observations are in agreement with polaronic charge transport above TC in the perovskite manganites; as electron hopping is responsible for bond disorder above TC, below the transition where eg carries are delocalized, any lattice displacements are uniformly averaged.Comment: 5 pages, 3 figures, submitted to Phys. Rev.

Grape Seed Proanthocyanidins Inhibit Melanoma Cell Invasiveness by Reduction of PGE2 Synthesis and Reversal of Epithelial-to-Mesenchymal Transition

Melanoma is the leading cause of death from skin disease due, in large part, to its propensity to metastasize. We have examined the effect of grape seed proanthocyanidins (GSPs) on melanoma cancer cell migration and the molecular mechanisms underlying these effects using highly metastasis-specific human melanoma cell lines, A375 and Hs294t. Using in vitro cell invasion assays, we observed that treatment of A375 and Hs294t cells with GSPs resulted in a concentration-dependent inhibition of invasion or cell migration of these cells, which was associated with a reduction in the levels of cyclooxygenase (COX)-2 expression and prostaglandin (PG) E2 production. Treatment of cells with celecoxib, a COX-2 inhibitor, or transient transfection of melanoma cells with COX-2 small interfering RNA, also inhibited melanoma cell migration. Treatment of cells with 12-O-tetradecanoylphorbol-13-acetate, an inducer of COX-2, enhanced the phosphorylation of ERK1/2, a protein of mitogen-activated protein kinase family, and subsequently cell migration whereas both GSPs and celecoxib significantly inhibited 12-O-tetradecanoylphorbol-13-acetate -promoted cell migration as well as phosphorylation of ERK1/2. Treatment of cells with UO126, an inhibitor of MEK, also inhibited the migration of melanoma cells. Further, GSPs inhibited the activation of NF-κB/p65, an upstream regulator of COX-2, in melanoma cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-κB, also inhibited cell migration. Additionally, inhibition of melanoma cell migration by GSPs was associated with reversal of epithelial-mesenchymal transition process, which resulted in an increase in the levels of epithelial biomarkers (E-cadherin and cytokeratins) while loss of mesenchymal biomarkers (vimentin, fibronectin and N-cadherin) in melanoma cells. Together, these results indicate that GSPs have the ability to inhibit melanoma cell invasion/migration by targeting the endogenous expression of COX-2 and reversing the process of epithelial-to-mesenchymal transition

Identification of a small molecule yeast TORC1 inhibitor with a flow cytometry-based multiplex screen

TOR (target of rapamycin) is a serine/threonine kinase, evolutionarily conserved from yeast to human, which functions as a fundamental controller of cell growth. The moderate clinical benefit of rapamycin in mTOR-based therapy of many cancers favors the development of new TOR inhibitors. Here we report a high throughput flow cytometry multiplexed screen using five GFPtagged yeast clones that represent the readouts of four branches of the TORC1 signaling pathway in budding yeast. Each GFP-tagged clone was differentially color-coded and the GFP signal of each clone was measured simultaneously by flow cytometry, which allows rapid prioritization of compounds that likely act through direct modulation of TORC1 or proximal signaling components. A total of 255 compounds were confirmed in dose-response analysis to alter GFP expression in one or more clones. To validate the concept of the high throughput screen, we have characterized CID 3528206, a small molecule most likely to act on TORC1 as it alters GFP expression in all five GFP clones in an analogous manner to rapamycin. We have shown that CID 3528206 inhibited yeast cell growth, and that CID 3528206 inhibited TORC1 activity both in vitro and in vivo with EC50s of 150 nM and 3.9 μM, respectively. The results of microarray analysis and yeast GFP collection screen further support the notion that CID 3528206 and rapamycin modulate similar cellular pathways. Together, these results indicate that the HTS has identified a potentially useful small molecule for further development of TOR inhibitors

Quality of care for hypertension in the United States

BACKGROUND: Despite heavy recent emphasis on blood pressure (BP) control, many patients fail to meet widely accepted goals. While access and adherence to therapy certainly play a role, another potential explanation is poor quality of essential care processes (QC). Yet little is known about the relationship between QC and BP control. METHODS: We assessed QC in 12 U.S. communities by reviewing the medical records of a randomly selected group of patients for the two years preceding our study. We included patients with either a diagnosis of hypertension or two visits with BPs of ≥140/90 in their medical records. We used 28 process indicators based on explicit evidence to assess QC. The indicators covered a broad spectrum of care and were developed through a modified Delphi method. We considered patients who received all indicated care to have optimal QC. We defined control of hypertension as BP < 140/90 in the most recent reading. RESULTS: Of 1,953 hypertensive patients, only 57% received optimal care and 42% had controlled hypertension. Patients who had received optimal care were more likely to have their BP under control at the end of the study (45% vs. 35%, p = .0006). Patients were more likely to receive optimal care if they were over age 50 (76% vs. 63%, p < .0001), had diabetes (77% vs. 71%, p = .0038), coronary artery disease (87% vs. 69%, p < .0001), or hyperlipidemia (80% vs. 68%, p < .0001), and did not smoke (73% vs. 66%, p = .0005). CONCLUSIONS: Higher QC for hypertensive patients is associated with better BP control. Younger patients without cardiac risk factors are at greatest risk for poor care. Quality measurement systems like the one presented in this study can guide future quality improvement efforts