bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral Protein Synthesis in the Ovine Fetus Near Term with Amino Acid Infusion and Insulin-Induced Hypoaminoacidemia
Authors: MacLachlan James N. , McCallum Jeremy D. , Smith Norman , Matushewski Brad , Richardson Bryan S.
Published: May 2010

Background: Studies during early development have shown that the precursor availability of amino acids directly affects protein synthesis both at the whole-body level and for select organ tissues, although this has not been studied for the brain. Objective: We utilized a mixed amino acid infusate and an insulin euglycemic clamp technique in the ovine fetus near term, with increases and decreases in circulating amino acid levels of ∼30 to 40% on average, and determined the impact on cerebral protein synthesis. Methods: Fetal sheep received a 6-hour infusion of Primene® 10% (amino acid infusate group) or a co-infusion of insulin and 10% dextrose (insulin/dextrose infusate group) together with a continuous infusion of L-[1-13C]-leucine. Measurements were obtained for fetal plasma leucine enrichment at steady-state and brain tissue intracellular free and protein-bound leucine enrichment at necropsy, followed by the determination of cerebral protein fractional synthetic rates (FSR). Results: Protein FSR for the cerebral cortex averaged ∼58 and ∼39%/day when using the intracellular free and plasma enrichment values for the precursor pool measurements, respectively, providing for maximal and minimal FSR values, and with little difference between the amino acid and insulin/dextrose groups, although significantly higher than respective values for the cerebellum. Conclusion: Accordingly, there was no evidence of a differential effect of increases versus decreases in circulating amino acids on cerebral protein synthesis as studied, which may be attributed to the saturable nature of the blood-brain barrier transporters for amino acids.
Synergetic Effects of Prednisolone and Olopatadine on Atopic Dermatitis Model of Hairless Mice
Authors: Kagawa Yoto , Izawa Kana , Yano Haruna , Kamei Chiaki
Published: May 2010

We investigated the synergetic effects of glucocorticoid and histamine H1 receptor antagonists on an atopic dermatitis model. Hairless mice were used in this study and an atopic dermatitis model was made by repeated application of 2,4,6-trinitrochlorobenzene. The effects of glucocorticoid, histamine H1 receptor antagonists, and the simultaneous use of these drugs were investigated by measuring scratching behavior, skin symptoms and nerve growth factor (NGF) in the skin. Topical application of prednisolone significantly inhibited scratching behavior, skin symptoms and NGF contents in the skin by repeated application. Olopatadine also showed a significant effect on scratching behavior and NGF contents in the skin, whereas chlorpheniramine showed no significant inhibitory effect on these indices. Furthermore, the combined use of prednisolone and olopatadine potentiated the inhibition of scratching behavior, skin symptoms, and NGF in the skin. From these findings, olopatadine potentiated the inhibitory effect of prednisolone on the symptoms of atopic dermatitis by inhibiting NGF.
Assessment of Anterior Chamber Depth Using Visante Optical Coherence Tomography, Slitlamp Optical Coherence Tomography, IOL Master, Pentacam and Orbscan IIz
Authors: Dinc Umut Asli , Gorgun Ebru , Oncel Banu , Yenerel Melda Nursal , Alimgil Levent
Published: May 2010

Aims: To assess and compare the anterior chamber depth (ACD) by different anterior segment imaging techniques. Methods: Eighty healthy eyes of 40 patients were recruited, and 3 consecutive measurements of ACD were determined prospectively utilizing Visante optical coherence tomography (OCT), slitlamp (SL) OCT, IOL Master, Pentacam and Orbscan IIz. The statistical significance of interdevice differences between measurements was evaluated by one-way ANOVA and Bland-Altman analysis. The repeatability of 3 consecutive measurements was analyzed by repeated-measures ANOVA. Results: The mean ACD was 2.98 ± 0.29, 2.85 ± 0.29, 3.33 ± 0.42, 2.93 ± 0.30 and 2.80 ± 0.29 mm with Visante OCT, SL-OCT, IOL Master, Pentacam and Orbscan IIz, respectively. All devices displayed a high intrasession repeatability (repeated-measures ANOVA, p > 0.05). ACD measurements obtained by the IOL Master were significantly greater compared to other devices. ACD values detected by Visante OCT and SL-OCT, Pentacam and Orbscan IIz were not clinically interchangeable, even though no statistically significant difference was detected. Conclusion: Although noncontact ACD measurements using all modalities were easy to handle and demonstrated good repeatability, the tested devices were not regarded as compatible. Hence, the clinician should take the different modalities into consideration during ACD assessment using various devices.
Oxane HD and Retinal Detachment Surgery in Routine Clinical Practice
Authors: Ang Ghee Soon , Murphy Anna Louise , Ng Wai Siene , Atta Hatem Riad
Published: May 2010

Background/Aims: To assess the outcomes and complications of endotamponade with Oxane HD following retinal detachment repair. Methods: Retrospective consecutive case series of inferior retinal detachment with Oxane HD endotamponade within a 3-year period. Results: Case notes for 18 eyes of 18 patients were reviewed. Four (22.2%) were total retinal detachments and 13 (72.2%) had proliferative vitreoretinopathy. The mean Oxane HD endotamponade and follow-up durations were 27 ± 38 and 66 ± 39 weeks, respectively. The eventual anatomic success rate was 77.8%, but without any significant difference in vision. Postoperative complications occurred in 14 (77.8%), including emulsification (6 eyes; 33.3%), epiretinal membrane (5 eyes; 27.8%), and posterior capsular opacification (4 eyes; 22.2%). Of the 14 eyes requiring intraoperative perfluorodecalin, 12 (85.7%) developed complications; all 5 (100%) eyes with direct exchange of perfluorodecalin with Oxane HD developed complications. Conclusion: Although useful for inferior retinal detachments, Oxane HD was associated with a relatively high rate of emulsification when compared to other series. Our series also suggests that prior use of perfluorodecalin intraoperatively, and in particular direct exchange of perfluorodecalin with Oxane HD, may be associated with an increased risk of intraocular complications.
Exercise Blood Pressure and Future Cardiovascular Death in Asymptomatic Individuals
Authors: Weiss Sandra A. , Blumenthal Roger S. , Sharrett A. Richey , Redberg Rita F. , Mora Samia
Published: May 2010

Background—

Individuals with exaggerated exercise blood pressure (BP) tend to develop future hypertension. It is controversial whether they have higher risk of death from cardiovascular disease (CVD).

Methods and Results—

A total of 6578 asymptomatic Lipid Research Clinics Prevalence Study participants (45% women; mean age, 46 years; 74% with untreated baseline BP <140/90 mm Hg [nonhypertensive]) performing submaximal Bruce treadmill tests were followed for 20 years (385 CVD deaths occurred). Systolic and diastolic BP at rest, Bruce stage 2, and maximal BP during exercise were significantly associated with CVD death. When we compared multivariate hazard ratios and 95% confidence intervals per 10/5-mm Hg BP increments, the association was strongest for rest BP (systolic, 1.21 [1.14 to 1.27]; diastolic, 1.20 [1.14 to 1.26]), then Bruce stage 2 BP (systolic, 1.09 [1.04 to 1.14]; diastolic, 1.09 [1.05 to 1.13]), then maximal exercise BP (systolic, 1.06 [1.01 to 1.10]; diastolic, 1.04 [1.01 to 1.08]). Overall, exercise BP was not significant after adjustment for rest BP. However, hypertension status modified the risk associated with exercise BP (
P
interaction
=0.03). Among nonhypertensives, whether they had normal BP (<120/80 mm Hg) or prehypertension, Bruce stage 2 BP >180/90 versus ≤180/90 mm Hg carried increased risk independent of rest BP and risk factors (adjusted hazard ratio for systolic, 1.96 [1.40 to 2.74],
P
<0.001; diastolic, 1.48 [1.06 to 2.06],
P
=0.02) and added predictive value (net reclassification improvement, systolic, 12.0% [−0.1% to 24.2%]; diastolic, 9.9% [−0.3% to 20.0%]; relative integrated discrimination improvement, 14.3% and 12.0%, respectively).

Conclusions—

In asymptomatic individuals, elevated exercise BP carried higher risk of CVD death but became nonsignificant after accounting for rest BP. However, Bruce stage 2 BP >180/90 mm Hg identified nonhypertensive individuals at higher risk of CVD death.
Cystatin C and Contrast-Induced Acute Kidney Injury
Authors: Briguori Carlo , Visconti Gabriella , Rivera Natalia V. , Focaccio Amelia , Golia Bruno , Giannone Rosalia , Castaldo Diletta , De Micco Francesca , Ricciardelli Bruno , Colombo Antonio
Published: May 2010

Background—

Cystatin C (CyC) is more sensitive than serum creatinine (sCr) to rapidly detect acute changes in renal function.

Methods and Results—

We measured CyC together with sCr in 410 consecutive patients with chronic kidney disease undergoing either coronary and/or peripheral angiography and/or angioplasty. sCr was assessed at baseline and 24 and 48 hours after contrast media exposure. CyC was assessed at baseline and at 24 hours. Major adverse events (including death of any cause and dialysis) at 12 months were assessed. At 48 hours after contrast media exposure, contrast-induced acute kidney injury (defined as a sCr increase ≥0.3 mg/dL) occurred in 34 patients (8.2%). A CyC increase concentration ≥10% at 24 hours after contrast media exposure was detected in 87 patients (21.2%). This was the best CyC cutoff for the early identification of patients at risk for contrast-induced acute kidney injury (negative predictive value=100%; positive predictive value=39.1%). According to the defined cutoffs (that is, increase in CyC ≥10% and sCr ≥0.3 mg/dL), major adverse events occurred in 16 of 297 patients (5.4%) without any cutoffs satisfied (group 1), in 9 of 49 patients (18.4%) with only a CyC increase ≥10% (group 2), and in 9 of 31 patients (29%) with both cutoffs satisfied (group 3). By logistic regression analysis, the independent predictors of major adverse events at 1 year were group 2 (odds ratio=2.52; 95% confidence interval, 1.17 to 5.41;
P
=0.02), group 3 (odds ratio=4.45; 95% confidence interval, 1.72 to 11.54;
P
=0.002), and baseline glomerular filtration rate (odds ratio=0.91; 95% confidence interval, 0.88 to 0.95;
P
<0.001).

Conclusions—

In patients with chronic kidney disease, CyC seems to be a reliable marker for the early diagnosis and prognosis of contrast-induced acute kidney injury.
COP-15 in Copenhagen: How the Merging of Movements Left Civil Society Out in the Cold
Authors: Fisher Dana R.
Published: May 2010

What happened to non-governmental organizations' participation at the COP-15 round of climate negotiations in Copenhagen? Although the climate regime has been seen as relatively open to civil society, everything changed in Copenhagen and civil society became increasingly disenfranchised. This article discusses the three main forces that led to civil society's disenfranchisement at this round of the climate negotiations: increased registration, poor planning by the Danish organizers and the United Nations Framework Convention on Climate Change Secretariat, and the merging of movements. I conclude by discussing implications of the increase in civil society disenfranchisement to the climate regime and to the study of global environmental politics more broadly.
Overlap Management in the World Trade Organization: Secretariat Influence on Trade-Environment Politics
Authors: Jinnah Sikina
Published: May 2010

This article builds on recent scholarship that explores the nature of secretariat influence in global governance. By combining data from interviews with WTO delegates and secretariat staff with document analysis, this study examines how the WTO secretariat is shaping trade-environment politics by using its bureaucratic authority to influence overlap management in the WTO. This study argues that secretariat influence is present, but varies in form across cases. It shows up in the forms noted by previous scholars in their examinations of UNEP secretariats (i.e. negotiation-facilitation, capacity building, and knowledge-brokering), but also in previously un-discussed forms of influence such as marketing convention norms, and litigation facilitation. It further argues that secretariat influence matters in that the WTO secretariat plays an important role in shaping the way trade-environment issues evolve within the WTO, shaping its own identity as a hybrid administrative-judicial organ, as well as in enhancing WTO legitimacy with the broader public.
Visualizing Spatial Heterogeneity of Western U.S. Climate Variability
Authors: Shinker Jacqueline J.
Published: May 2010

Monthly climatologies (1971–2000 monthly averages) for stations in the western United States, obtained from the NOAA/National Climatic Data Center (NCDC), are used to illustrate the spatial variations in the annual cycle of climate. Animated map sequences of temperature and precipitation, their average, intermonthly changes, and the local timing of annual maxima or minima provide a comprehensive spatiotemporal baseline of regional climate. The animated maps illustrate three scales of variation: 1) broadscale patterns related to the annual cycle of insolation and hemispheric-scale atmospheric circulation features; 2) mesoscale patterns related to location on the continent and the influence of specific regional circulation features like those associated with the North American monsoon; and 3) smaller-scale spatial variations, related to the mediation by local physiography of the influence of large-scale circulation. Although most western U.S. stations have temperature maxima in July, a delay occurs at stations along the West Coast and interior Washington, northern Idaho, and Montana. A seesaw pattern of precipitation maxima is evident between coastal areas (winter dominated) and the interior (summer dominated). Cluster analyses of the ratio of monthly-to-annual precipitation values for each station identify regions with similar annual cycles of precipitation. Regions of high spatial heterogeneity in the timing of when precipitation occurs include the northern Rocky Mountains, Utah, Arizona, and northwestern Montana. The superimposition of these three scales of spatial variability leads to steep gradients and, in some regions, considerable spatial heterogeneity in annual precipitation. The regional patterns of precipitation heterogeneity highlight vulnerability to drought, especially in regions of the interior west that do not have a dominant precipitation month or season.
Pattern-Based Evaluation of Coupled Meteorological and Air Quality Models
Authors: Beaver Scott , Tanrikulu Saffet , Palazoglu Ahmet , Singh Angadh , Soong Su-Tzai , Jia Yiqin , Tran Cuong , Ainslie Bruce , Steyn Douw G.
Published: May 2010

A novel pattern-based model evaluation technique is proposed and demonstrated for air quality models (AQMs) driven by meteorological model (MM) output. The evaluation technique is applied directly to the MM output; however, it is ultimately used to gauge the performance of the driven AQM. This evaluation of AQM performance based on MM performance is a major advance over traditional evaluation methods. First, meteorological cluster analysis is used to assign the days of a historical measurement period among a small number of weather patterns having distinct air quality characteristics. The clustering algorithm groups days sharing similar empirical orthogonal function (EOF) representations of their measurements. In this study, EOF analysis is used to extract space–time patterns in the surface wind field reflecting both synoptic and mesoscale influences. Second, simulated wind fields are classified among the determined weather patterns using the measurement-derived EOFs. For a given period, the level of agreement between the observation-based clustering labels and the simulation-based classification labels is used to assess the validity of the simulation results. Mismatches occurring between the two sets of labels for a given period imply inaccurately simulated conditions. Moreover, the specific nature of a mismatch can help to diagnose the downstream effects of improperly simulated meteorological fields on AQM performance. This pattern-based model evaluation technique was applied to extended simulations of fine particulate matter (PM2.5) covering two winter seasons for the San Francisco Bay Area of California.
Normalizing Air–Sea Flux Coefficients for Horizontal Homogeneity, Stationarity, and Neutral Stratification
Authors: Geernaert G. L.
Published: May 2010

Monin–Obukhov similarity (MOS) theory is routinely applied over the ocean to describe surface layer profiles of wind speed, temperature, and gas concentrations. Using this theory, fluxes are in turn estimated based on the best available parameterizations of normalized flux coefficients: for example, neutral flux coefficients. Flux coefficients can vary with environmental conditions. Because it is generally assumed that the domain of interest must be characterized by spatially homogeneous and steady-state conditions, systematic violations of the assumptions may lead to significant uncertainties in flux estimates. In this paper, the author has extended MOS theory to accommodate nonstationarity and spatial inhomogeneity in the representation of the normalized drag coefficient, Stanton number, and Dalton number. The author illustrates the importance of his theoretical extension, based on a reexamination of a historical air–sea interaction dataset obtained from the North Sea.
Modeling, Error Analysis, and Evaluation of Dual-Polarization Variables Obtained from Simultaneous Horizontal and Vertical Polarization Transmit Radar. Part I: Modeling and Antenna Errors
Authors: Hubbert J. C. , Ellis S. M. , Dixon M. , Meymaris G.
Published: May 2010

In this two-part paper the biases of polarimetric variables from simultaneous horizontally and vertically transmitted (SHV) data are investigated. Here, in Part I, a radar-scattering model is developed and antenna polarization errors are investigated and estimated. In Part II, experimental data from the National Center for Atmospheric Research S-band dual-polarization Doppler radar (S-Pol) and the National Severe Storms Laboratory polarimetric Weather Surveillance Radar-1988 Doppler (WSR-88D) radar, KOUN, are used to illustrate biases in differential reflectivity (Zdr). The biases in the SHV polarimetric variables are caused by cross coupling of the horizontally (H) and vertically (V) polarized signals. The cross coupling is caused by the following two primary sources: 1) the nonzero mean canting angle of the propagation medium and 2) antenna polarization errors. The biases are strong functions of the differential propagation phase (ϕdp) and the phase difference between the H and V transmitted field components. The radar-scattering model developed here allows for the evaluation of biases caused by cross coupling as a function of ϕdp, with the transmission phase difference as a parameter. Also, antenna polarization errors are estimated using solar scan measurements in combination with estimates of the radar system’s linear depolarization ratio (LDR) measurement limit. Plots are given that show expected biases in SHV Zdr for various values of the LDR system’s limit.
Modeling, Error Analysis, and Evaluation of Dual-Polarization Variables Obtained from Simultaneous Horizontal and Vertical Polarization Transmit Radar. Part II: Experimental Data
Authors: Hubbert J. C. , Ellis S. M. , Dixon M. , Meymaris G.
Published: May 2010

In this second article in a two-part work, the biases of weather radar polarimetric variables from simultaneous horizontally and vertically transmit (SHV) data are investigated. The biases are caused by cross coupling of the simultaneously transmitted vertical (V) and horizontal (H) electric fields. There are two primary causes of cross coupling: 1) the nonzero mean canting angle of the propagation medium (e.g., canted ice crystals) and 2) antenna polarization errors. Given herein are experimental data illustrating both bias sources. In Part I, a model is developed and used to quantify cross coupling and its impact on polarization measurements. Here, in Part II, experimental data from the National Center for Atmospheric Research’s (NCAR’s) S-band dual-polarimetric Doppler radar (S-Pol) and the National Severe Storms Laboratory’s polarimetric Weather Surveillance Radar-1988 Doppler (WSR-88D), KOUN, are used to illustrate biases in differential reflectivity (Zdr). The S-Pol data are unique: both SHV data and fast alternating H and V transmit (FHV) data are gathered in close time proximity, and thus the FHV data provide “truth” for the SHV data. Specifically, the SHV Zdr bias in rain caused by antenna polarization errors is clearly demonstrated by the data. This has not been shown previously in the literature.
Quality Assurance Procedures for Mesoscale Meteorological Data
Authors: Fiebrich Christopher A. , Morgan Cynthia R. , McCombs Alexandria G. , Hall Peter K. , McPherson Renee A.
Published: May 2010

Mesoscale meteorological data present their own challenges and advantages during the quality assurance (QA) process because of their variability in both space and time. To ensure data quality, it is important to perform quality control at many different stages (e.g., sensor calibrations, automated tests, and manual assessment). As part of an ongoing refinement of quality assurance procedures, meteorologists with the Oklahoma Mesonet continually review advancements and techniques employed by other networks. This article’s aim is to share those reviews and resources with scientists beginning or enhancing their own QA program. General QA considerations, general automated tests, and variable-specific tests and methods are discussed.
Evaluation of Planetary Boundary Layer Scheme Sensitivities for the Purpose of Parameter Estimation
Authors: Nielsen-Gammon John W. , Hu Xiao-Ming , Zhang Fuqing , Pleim Jonathan E.
Published: May 2010

Meteorological model errors caused by imperfect parameterizations generally cannot be overcome simply by optimizing initial and boundary conditions. However, advanced data assimilation methods are capable of extracting significant information about parameterization behavior from the observations, and thus can be used to estimate model parameters while they adjust the model state. Such parameters should be identifiable, meaning that they must have a detectible impact on observable aspects of the model behavior, their individual impacts should be a monotonic function of the parameter values, and the various impacts should be clearly distinguishable from each other.

A sensitivity analysis is conducted for the parameters within the Asymmetrical Convective Model, version 2 (ACM2) planetary boundary layer (PBL) scheme in the Weather Research and Forecasting model in order to determine the parameters most suited for estimation. A total of 10 candidate parameters are selected from what is, in general, an infinite number of parameters, most being implicit or hidden. Multiple sets of model simulations are performed to test the sensitivity of the simulations to these 10 particular ACM2 parameters within their plausible physical bounds. The most identifiable parameters are found to govern the vertical profile of local mixing within the unstable PBL, the minimum allowable diffusivity, the definition of the height of the unstable PBL, and the Richardson number criterion used to determine the onset of turbulent mixing in stable stratification. Differences in observability imply that the specific choice of parameters to be estimated should depend upon the characteristics of the observations being assimilated.
Observational Analysis of an Upper-Level Inverted Trough during the 2004 North American Monsoon Experiment
Authors: Finch Zachary O. , Johnson Richard H.
Published: May 2010

Upper-level inverted troughs (IVs) associated with midlatitude breaking Rossby waves or tropical upper-troposphere troughs (TUTTs) have been identified as important contributors to the variability of rainfall in the North American monsoon (NAM) region. However, little attention has been given to the dynamics of these systems owing to the sparse observational network over the NAM region. High temporal and spatial observations taken during the 2004 North American Monsoon Experiment (NAME) are utilized to analyze a significant IV that passed over northwestern Mexico from 10 to 13 July 2004. The Colorado State University gridded dataset, which is independent of model analysis over land, is the primary data source used in this study.

Results show that the 10–13 July IV disturbance was characterized by a warm anomaly around 100 hPa and a cold anomaly that extended from 200 to 700 hPa. The strongest cyclonic circulation was in the upper levels around 200 hPa. Quasigeostrophic (QG) diagnostics indicate that the upper-level low forced weak subsidence (weak rising motion) to the west (east) of its center. Net downward motion to the west was a result of the Laplacian of thermal advection (forcing subsidence) outweighing differential vorticity advection (forcing weak upward motion). Despite the QG forcing of downward motion west of the upper-level IV, enhanced convection occurred west of the IV center along the western slopes of the Sierra Madre Occidental (SMO). This seemingly contradictory behavior can be explained by noting that the upper-level IV induced a midlevel cyclonic circulation, with northeasterly (southeasterly) midlevel flow to the west (east) of its center. Increased mesoscale organization of convection along the SMO foothills was found to be collocated with IV-enhanced northeasterly midlevel flow and anomalous northeasterly shear on the western (leading) flank of the system. It is proposed that the upper-level IV increased the SMO-perpendicular midlevel flow as well as the wind shear, thereby creating an environment favorable for convective storms to grow upscale as they moved off the high terrain.
Identification of the secondary actuator dynamics at frequencies beyond the Nyquist Rate in Dual-Stage Actuator Hard Disk Drive systems
Authors: Nagashima Masaki , Nakagawa Shinsuke
Published: May 2010

In Hard Disk Drive (HDD) head positioning control systems, the system output can be observed only at fixed finite time intervals. Identification of the plant dynamics embedded in such an inherently sampled-data system requires special considerations to avoid the aliasing effect caused by the sampling operation. In this paper, non-parametric algorithms to identify the secondary actuator dynamics in a Dual-Stage Actuator HDD system are investigated. Identification methods with continuous-time and discrete-time excitation input are proposed. In the discrete-time method, a multirate digital—analogue converter and multirate filters are employed to reduce the aliasing effect. Numerical simulation and experimental results are presented to show the effectiveness of the proposed methods.
Ethnic and Racial Differences of Baseline Stroke Knowledge in a “Stroke Belt” Community
Authors: Biederman Donna J. , Sienkiewicz Holly C. , Bibeau Daniel L. , Chase Chere M. , Spann LaPronda I. , Romanchuck Robert , Aronson Robert E. , Schulz Mark R. , Tiberia-Galka Angela
Published: May 2010

Acute stroke is often a treatable condition; however, intervention is time dependent and typically should ensue within 3 hr from onset of symptoms. The ability of individuals to understand stroke risk factors to reduce individual risk and to recognize warning signs and symptoms of stroke as signals to initiate medical care is paramount to decreasing stroke-related morbidity and mortality. This descriptive study presents ethnic and racial differences of baseline stroke knowledge among residents ( n = 1,904) of two North Carolina counties situated in the Stroke Belt. Findings suggest a global stroke knowledge deficit that is more pronounced among Hispanics. Future community stroke education campaigns need to consider various educational mediums and outlets to ensure inclusion of persons at highest risk for stroke. Suggestions are provided for possible content of future stroke knowledge and prevention campaigns.
A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial
Authors: Röllig Christoph , Thiede Christian , Gramatzki Martin , Aulitzky Walter , Bodenstein Heinrich , Bornhäuser Martin , Platzbecker Uwe , Stuhlmann Reingard , Schuler Ulrich , Soucek Silke , Kramer Michael , Mohr Brigitte , Oelschlaegel Uta , Stölzel Friedrich , von Bonin Malte , Wermke Martin , Wandt Hannes , Ehninger Gerhard , Schaich Markus ,   for the Study Alliance Leukemia
Published: May 2010

We present an analysis of prognostic factors derived from a trial in patients with acute myeloid leukemia older than 60 years. The AML96 trial included 909 patients with a median age of 67 years (range, 61-87 years). Treatment included cytarabine-based induction therapy followed by 1 consolidation. The median follow-up time for all patients is 68 months (5.7 years). A total of 454 of all 909 patients reached a complete remission (50%). Five-year overall survival (OS) and disease-free survival were 9.7% and 14%, respectively. Multivariate analyses revealed that karyotype, age, NPM1 mutation status, white blood cell count, lactate dehydrogenase, and CD34 expression were of independent prognostic significance for OS. On the basis of the multivariate Cox model, an additive risk score was developed that allowed the subdivision of the largest group of patients with an intermediate-risk karyotype into 2 groups. We are, therefore, able to distinguish 4 prognostic groups: favorable risk, good intermediate risk, adverse intermediate risk, and high risk. The corresponding 3-year OS rates were 39.5%, 30%, 10.6%, and 3.3%, respectively. The risk model allows further stratification of patients with intermediate-risk karyotype into 2 prognostic groups with implications for the therapeutic strategy. This study was registered at www.clinicaltrials.gov as #NCT00180115.
A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1
Authors: Lukina Elena , Watman Nora , Arreguin Elsa Avila , Banikazemi Maryam , Dragosky Marta , Iastrebner Marcelo , Rosenbaum Hanna , Phillips Mici , Pastores Gregory M. , Rosenthal Daniel I. , Kaper Mathilde , Singh Tejdip , Puga Ana Cristina , Bonate Peter L. , Peterschmitt M. Judith
Published: May 2010

Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia. The composite primary efficacy end point required improvement after 52 weeks in at least 2 of these 3 disease manifestations and was met by 77% (95% confidence interval [CI] = 58%-89%) of all patients and 91% (95% CI = 72%-98%) of the 22 patients completing 52 weeks. Statistically significant improvements occurred in mean hemoglobin level (1.62 g/dL; 95% CI =1.05-2.18 g/dL), platelet count (40.3%; 95% CI = 23.7-57.0 g/dL), spleen volume (−38.5%; 95% CI = −43.5%-−33.5%), liver volume (−17.0%; 95% CI = −21.6%-12.3%), and lumbar spine bone mineral density (0.31 Z-score; 95% CI = 0.09-0.53). Elevated biomarkers (chitotriosidase; chemokine CCL18; angiotensin-converting enzyme; tartrate-resistant acid phosphatase) decreased by 35% to 50%. Plasma glucosylceramide and ganglioside GM3 normalized. Eliglustat tartrate was well tolerated: 7 mild, transient adverse events in 6 patients were considered treatment-related. Individual pharmacokinetics varied; mean time to maximal observed concentration was 2.3 hours and mean half-life was 6.8 hours. Eliglustat tartrate appears to be a promising oral treatment for GD1. This study is registered at www.clinicaltrials.gov as #NCT00358150.
Dyslipidemia after allogeneic hematopoietic stem cell transplantation: evaluation and management
Authors: Griffith Michelle L. , Savani Bipin N. , Boord Jeffrey B.
Published: May 2010

Currently, approximately 15 000 to 20 000 patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) annually throughout the world, with the number of long-term survivors increasing rapidly. In long-term follow-up after transplantation, the focus of care moves beyond cure of the original disease to the identification and treatment of late effects after HSCT. One of the more serious complications is therapy-related cardiovascular disease. Long-term survivors after HSCT probably have an increased risk of premature cardiovascular events. Cardiovascular complications related to dyslipidemia and other risk factors account for a significant proportion of late nonrelapse morbidity and mortality. This review addresses the risk and causes of dyslipidemia and impact on cardiovascular complications after HSCT. Immunosuppressive therapy, chronic graft-versus-host disease, and other long-term complications influence the management of dyslipidemia. There are currently no established guidelines for evaluation and management of dyslipidemia in HSCT patients; in this review, we have summarized our suggested approach in the HSCT population.
The spectrum of resistance in SR/CR mice: the critical role of chemoattraction in the cancer/leukocyte interaction
Authors: Riedlinger Gregory , Adams Jonathan , Stehle John R , Blanks Michael J , Sanders Anne M , Hicks Amy M , Willingham Mark C , Cui Zheng
Published: May 2010

Background

Spontaneous regression/complete resistance (SR/CR) mice are a unique colony of mice that possess an inheritable, natural cancer resistance mediated primarily by innate cellular immunity. This resistance is effective against sarcoma 180 (S180) at exceptionally high doses and these mice remain healthy.

Methods

In this study, we challenged SR/CR mice with additional lethal transplantable mouse cancer cell lines to determine their resistance spectrum. The ability of these transplantable cancer cell lines to induce leukocyte infiltration was quantified and the percentage of different populations of responding immune cells was determined using flow cytometry.

Results

In comparison to wild type (WT) mice, SR/CR mice showed significantly higher resistance to all cancer cell lines tested. However, SR/CR mice were more sensitive to MethA sarcoma (MethA), B16 melanoma (B16), LL/2 lung carcinoma (LL/2) and J774 lymphoma (J774) than to sarcoma 180 (S180) and EL-4 lymphoma (EL-4). Further mechanistic studies revealed that this lower resistance to MethA and LL/2 was due to the inability of these cancer cells to attract SR/CR leukocytes, leading to tumor cell escape from resistance mechanism. This escape mechanism was overcome by co-injection with S180, which could attract SR/CR leukocytes allowing the mice to resist higher doses of MethA and LL/2. S180-induced cell-free ascites fluid (CFAF) co-injection recapitulated the results obtained with live S180 cells, suggesting that this chemoattraction by cancer cells is mediated by diffusible molecules. We also tested for the first time whether SR/CR mice were able to resist additional cancer cell lines prior to S180 exposure. We found that SR/CR mice had an innate resistance against EL-4 and J774.

Conclusions

Our results suggest that the cancer resistance in SR/CR mice is based on at least two separate processes: leukocyte migration/infiltration to the site of cancer cells and recognition of common surface properties on cancer cells. The infiltration of SR/CR leukocytes was based on both the innate ability of leukocytes to respond to chemotactic signals produced by cancer cells and on whether cancer cells produced these chemotactic signals. We found that some cancer cells could escape from SR/CR resistance because they did not induce infiltration of SR/CR leukocytes. However, if infiltration of leukocytes was induced by co-injection with chemotactic factors, these same cancer cells could be effectively recognized and killed by SR/CR leukocytes.
Factors affecting recruitment and retention of community health workers in a newborn care intervention in Bangladesh
Authors: Rahman Syed Moshfiqur , Ali Nabeel Ashraf , Jennings Larissa , Seraji M Habibur R , Mannan Ishtiaq , Shah Rasheduzzaman , Al-Mahmud Arif Billah , Bari Sanwarul , Hossain Daniel , Das Milan Krishna , Baqui Abdullah H , El Arifeen Shams , Winch Peter J
Published: May 2010

Background

Well-trained and highly motivated community health workers (CHWs) are critical for delivery of many community-based newborn care interventions. High rates of CHW attrition undermine programme effectiveness and potential for implementation at scale. We investigated reasons for high rates of CHW attrition in Sylhet District in north-eastern Bangladesh.

Methods

Sixty-nine semi-structured questionnaires were administered to CHWs currently working with the project, as well as to those who had left. Process documentation was also carried out to identify project strengths and weaknesses, which included in-depth interviews, focus group discussions, review of project records (i.e. recruitment and resignation), and informal discussion with key project personnel.

Results

Motivation for becoming a CHW appeared to stem primarily from the desire for self-development, to improve community health, and for utilization of free time. The most common factors cited for continuing as a CHW were financial incentive, feeling needed by the community, and the value of the CHW position in securing future career advancement. Factors contributing to attrition included heavy workload, night visits, working outside of one's home area, familial opposition and dissatisfaction with pay.

Conclusions

The framework presented illustrates the decision making process women go through when deciding to become, or continue as, a CHW. Factors such as job satisfaction, community valuation of CHW work, and fulfilment of pre-hire expectations all need to be addressed systematically by programs to reduce rates of CHW attrition.
Identifying essential genes in bacterial metabolic networks with machine learning methods
Authors: Plaimas Kitiporn , Eils Roland , König Rainer
Published: May 2010

Background

Identifying essential genes in bacteria supports to identify potential drug targets and an understanding of minimal requirements for a synthetic cell. However, experimentally assaying the essentiality of their coding genes is resource intensive and not feasible for all bacterial organisms, in particular if they are infective.

Results

We developed a machine learning technique to identify essential genes using the experimental data of genome-wide knock-out screens from one bacterial organism to infer essential genes of another related bacterial organism. We used a broad variety of topological features, sequence characteristics and co-expression properties potentially associated with essentiality, such as flux deviations, centrality, codon frequencies of the sequences, co-regulation and phyletic retention. An organism-wise cross-validation on bacterial species yielded reliable results with good accuracies (area under the receiver-operator-curve of 75% - 81%). Finally, it was applied to drug target predictions for Salmonella typhimurium. We compared our predictions to the viability of experimental knock-outs of S. typhimurium and identified 35 enzymes, which are highly relevant to be considered as potential drug targets. Specifically, we detected promising drug targets in the non-mevalonate pathway.

Conclusions

Using elaborated features characterizing network topology, sequence information and microarray data enables to predict essential genes from a bacterial reference organism to a related query organism without any knowledge about the essentiality of genes of the query organism. In general, such a method is beneficial for inferring drug targets when experimental data about genome-wide knockout screens is not available for the investigated organism.
The role of renin angiotensin system inhibition in kidney repair
Authors: van der Meer Irene M , Cravedi Paolo , Remuzzi Giuseppe
Published: May 2010

Chronic kidney diseases share common pathogenic mechanisms that, independently from the initial injury, lead to glomerular hyperfiltration, proteinuria, and progressive renal scarring and function loss. Inhibition of the renin angiotensin system (RAS) has been consistently found to reduce or halt the progressive deterioration of renal function through reduction of blood pressure and proteinuria, the two main determinants of renal function decline. In few instances, RAS inhibition may even promote amelioration of the glomerular filtration rate. Animal data suggest that chronic therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor type I blockers promotes regression of glomerulosclerosis, even in later phases of the disease. In humans, studies investigating the effect of angiotensin II inhibition on renal structural changes have shown inconsistent results, possibly due to small numbers and/or short duration of follow-up. Whether regression of glomerulosclerosis relies on a direct regenerative effect of RAS inhibition or on spontaneous kidney self-repair after the injury has been removed is still unknown. Improved understanding of mechanisms that promote renal regeneration may help in designing specific therapies to prevent the development of end-stage renal disease. This is a desirable goal, considering the economic burden of chronic kidney diseases and their effect on morbidity and mortality.
Inhibiting miRNA in Caenorhabditis elegans using a potent and selective antisense reagent
Authors: Zheng Genhua , Ambros Victor , Li Wen-hong
Published: May 2010

Background

Antisense reagents can serve as efficient and versatile tools for studying gene function by inhibiting nucleic acids in vivo. Antisense reagents have particular utility for the experimental manipulation of the activity of microRNAs (miRNAs), which are involved in the regulation of diverse developmental and physiological pathways in animals. Even in traditional genetic systems, such as the nematode Caenorhabditis elegans, antisense reagents can provide experimental strategies complementary to mutational approaches. Presently no antisense reagents are available for inhibiting miRNAs in the nematode C. elegans.

Results

We have developed a new class of fluorescently labelled antisense reagents to inhibit miRNAs in developing worms. These reagents were synthesized by conjugating dextran with 2'-O-methyl oligoribonucleotide. The dextran-conjugated antisense reagents can be conveniently introduced into the germline of adult hermaphrodites and are transmitted to their progeny, where they efficiently and specifically inhibit a targeted miRNA in different tissues, including the hypodermis, the vulva and the nervous system. We show that these reagents can be used combinatorially to inhibit more than one miRNA in the same animal.

Conclusion

This class of antisense reagents represents a new addition to the toolkit for studying miRNA in C. elegans. Combined with numerous mutants or reporter stains available, these reagents should provide a convenient approach to examine genetic interactions that involve miRNA, and may facilitate studying functions of miRNAs, especially ones whose deletion strains are difficult to generate.

See related research article: http://jbiol.com/content/9/3/20
Prostate-Specific Antigen Kinetics During Follow-Up Are an Unreliable Trigger for Intervention in a Prostate Cancer Surveillance Program
Authors: Ross Ashley E. , Loeb Stacy , Landis Patricia , Partin Alan W. , Epstein Jonathan I. , Kettermann Anna , Feng Zhaoyong , Carter H. Ballentine , Walsh Patrick C.
Published: May 2010

Purpose

To assess the predictive ability of prostate-specific antigen (PSA) velocity (PSAV) and doubling time (PSADT) for biopsy progression and adverse pathology at prostatectomy among men with low-risk prostate cancer enrolled on an active-surveillance program.

Methods

We evaluated 290 men who met criteria for active surveillance (ie, PSA density < 0.15 ng/mL/cm3and Gleason score ≤ 6 with no pattern ≥ 4, involving ≤ 2 cores with cancer, and ≤ 50% involvement of any core by cancer) with two or more serial PSA measurements after diagnosis from 1994 to 2008. Follow-up included twice-yearly digital rectal exam and PSA measurements and yearly surveillance biopsy. Treatment was recommended for biopsy progression (ie, Gleason score ≥ 7, or > 2 positive cores, or > 50% core involvement). Sensitivity and specificity of postdiagnostic PSAV and PSADT were explored by using receiver operating characteristic (ROC) analysis.

Results

Overall, 188 (65%) men remained on active surveillance, and 102 (35%) developed biopsy progression at a median follow-up of 2.9 years. PSADT was not significantly associated with subsequent adverse biopsy findings (P = .83), and PSAV was marginally significant (P = .06). No PSAV or PSADT cut point had both high sensitivity and specificity (area under the curve, 0.61 and 0.59, respectively) for biopsy progression. In those who eventually underwent radical prostatectomy, PSAV (P = .79) and PSADT (P = .87) were not associated with the presence of unfavorable surgical pathology.

Conclusion

Postdiagnostic PSA kinetics do not reliably predict adverse pathology and should not be used to replace annual surveillance biopsy for monitoring men on active surveillance.
Not the Witness We Wished For: Testimony in Jonathan Littell's Kindly Ones
Authors: Razinsky Liran
Published: May 2010

This essay examines Jonathan Littell's novel The Kindly Ones (Les bienveillantes) as a project of bearing witness. It turns a critical eye on the role played by the poetics of excess and transgression, on the novel's historical aspects (dates, events, and other details), and on the interplay among them; it inquires as well into the literary construction of testimonial authority.
Considerations When Upgrading Your PDA/Smartphone
Authors: Fox Brent I. , Felkey Bill G.
Published: May 2010

If you have followed our column since its inception, you may recall that several years ago we wrote about the process of selecting your portable device platform. As a health care professional, you are aware of the rapidity in which technology changes and advancements occur in all aspects of care delivery. We recently addressed the iPhone as a unique device but we believe it is also important — in today's personal digital assistant (PDA)/Smartphone environment — to write globally about upgrading, migrating, or purchasing your first device. This column addresses that process.
Heart Failure with Sunitinib; Prolonged QT Interval, Syncope, and Delirium with Galantamine; Memantine-Induced Hepatitis; Cabergoline-Associated Erythema Nodosum; “Sleep Driving” and the Use of Nonbenzodiazepine Hypnotics; Atypical Fractures in Postmenopausal Women Taking Alendronate; Drug-Related Problems in Patients with Human Immunodeficiency Virus
Authors: Shuster Joel
Published: May 2010

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the Food and Drug Administration's (FDA) medWatch program (800-FDA-1088). If you have reported an interesting preventable ADR to medWatch, please consider sharing the account with our readers.