bluuebunny/crossref_metadata_2025 huggingface dataset:
New Intra-arterial Drug Delivery System for the Treatment of Liver Cancer: Preclinical Assessment in a Rabbit Model of Liver Cancer
Authors: Hong Kelvin , Khwaja Afsheen , Liapi Eleni , Torbenson Michael S. , Georgiades Cristos S. , Geschwind Jean-Francois H.
Published: April 2006

Background: In the fight against cancer, new drug delivery systems are attractive to improve drug targeting of tumors, maximize drug potency, and minimize systemic toxicity. We studied a new drug delivery system comprising microspheres, with unique properties allowing delivery of large amounts of drugs to tumors for a prolonged time, thereby decreasing plasma levels. Liver tumors, unlike nontumorous liver, draw most of their blood supply from the hepatic artery. Exploiting this property, we delivered drug-eluting microspheres/beads (DEB) loaded with doxorubicin, intra-arterially, in an animal model of liver cancer (Vx-2).

Purpose: The purpose of our study was to determine the pharmacokinetics and tumor-killing efficacy of DEB.

Results: Our results show that plasma concentration of doxorubicin was minimal in the animals treated with DEB at all time points (0.009-0.05 μmol/L), suggesting high tumor retention of doxorubicin. This was significantly lower (70-85% decrease in plasma concentration) than control animals treated with doxorubicin intra-arterially. Within the tumor, doxorubicin concentration peaked at 3 days (413.5 nmol/g), remaining high to 7 days (116.7 nmol/g) before declining at 14 days (41.76 nmol/g), indicating continuous doxorubicin elution from beads. In control animals, peak tumor concentration of doxorubicin was 0.09 nmol/g. Tumor necrosis (approaching 100%) was greatest at 7 days, with minimal adverse local side effects reflected in liver function tests results. The plasma concentration of doxorubicinol (doxorubicin main metabolite) was minimal.

Conclusions: Our results support the concept of DEBs as an effective way to deliver drugs to tumor. This new technology may prove to be a useful weapon against liver cancer.
Potential and Toxicity of Intravesical Pemetrexed: a Preclinical Study in Pigs
Authors: Hendricksen Kees , Moonen Paula M.J. , van der Heijden Antoine G. , Molkenboer-Kuenen Janneke , Hulsbergen-van de Kaa Christina A. , Witjes J. Alfred
Published: April 2006

Purpose: In search for a new drug for intravesical use in superficial urothelial cell carcinoma of the bladder, a pig model is used for pharmacokinetics and toxicity measurements after intravesically administered pemetrexed.

Experimental Design: In the dose escalation phase, two groups of two pigs received 5 and 10 mg/kg pemetrexed intravesically; four groups of three pigs received 15, 20, 25, and 30 mg/kg, respectively. The well-being of the animals was monitored. Blood was studied for pharmacokinetic analysis and signs of myelosuppression. Posttreatment urine samples were collected to measure the concentration of pemetrexed after instillation. Twenty-four hours posttreatment, the animals were cystectomized and sacrificed. Histopathologic examination of the bladder wall was done. In the second study phase, five pigs were instilled weekly with the maximum tested dose for 6 weeks. The same methods were applied.

Results: All doses (5-30 mg/kg) in the first study phase were well tolerated, enabling the use of 30 mg/kg in the second study phase. In both study phases, the pigs' well-being was not influenced. Full blood counts showed no sign of myelosuppression. Systemic absorption was not observed. Urine pemetrexed concentrations remained almost unchanged. Histopathologic examination of the bladder wall did not reveal significant abnormalities. Bladder mucosa remained intact at any time, without hemorrhage.

Conclusions: Intravesically administered pemetrexed in pigs is well tolerated, not absorbed systemically, and causes no bladder wall toxicity.
Immunohistochemical and Genetic Evaluation of Deoxycytidine Kinase in Pancreatic Cancer: Relationship to Molecular Mechanisms of Gemcitabine Resistance and Survival
Authors: Sebastiani Valeria , Ricci Francesca , Rubio-Viquiera Belen , Kulesza Piotr , Yeo Charles J. , Hidalgo Manuel , Klein Alison , Laheru Daniel , Iacobuzio-Donahue Christine A.
Published: April 2006

Gemcitabine is considered the standard first-line therapy for patients with advanced pancreatic cancer. More recent strategies have focused on improving the efficacy of gemcitabine by either improving the method of delivery or by combining gemcitabine with other non-cross-resistant chemotherapy agents or with small-molecule drugs. However, the clinical benefits, response rates, and duration of responses have been modest. Deoxycytidine kinase (dCK) is the rate-limiting enzyme involved in the metabolism of gemcitabine. The expression of dCK has been postulated to be correlative of gemcitabine resistance. We determined the relationship of dCK immunohistochemical protein expression and/or genetic status of dCK in a panel of human pancreatic cancer tissues and pancreatic cancer cell lines and determined the relationship of these variables to the clinical outcome of patients treated with gemcitabine. We report that dCK protein expression is expressed in the majority of pancreatic cancers analyzed (40 of 44 cases, 91%) and showed a range of labeling intensities ranging from 1+ (labeling weaker in intensity than normal lymphocytes present in same section) to 3+ (labeling greater in intensity than normal lymphocytes present in same section). When labeling intensity was compared with survival, low dCK expression (1+ labeling) was correlated with both overall survival (P < 0.009) and progression-free survival following gemcitabine treatment (P < 0.04). Low dCK labeling intensity was also significantly correlated with patient age (70.3 ± 8.1 versus 59.8 ± 7.4 years; P < 0.0006), suggesting that age-related methylation of the dCK gene may account in part for the observed differences. Sequencing of the entire dCK coding sequence in 17 cell lines and 9 patients' cancer tissues with disease progression while on gemcitabine did not identify any mutations, suggesting that genetic alterations of dCK are not a common mechanism of resistance to gemcitabine for this tumor type. Moreover, dCK labeling showed similar patterns and intensities of labeling among matched pretreatment and post-treatment tissues. In summary, pretreatment levels of dCK protein are most correlated with overall survival following gemcitabine treatment and are stable even after resistance to gemcitabine is clinically documented.
Association of DNA Repair and Steroid Metabolism Gene Polymorphisms with Clinical Late Toxicity in Patients Treated with Conformal Radiotherapy for Prostate Cancer
Authors: Damaraju Sambasivarao , Murray David , Dufour Jennifer , Carandang Diana , Myrehaug Sten , Fallone Gino , Field Colin , Greiner Russell , Hanson John , Cass Carol E. , Parliament Matthew
Published: April 2006

Objective: To explore the possible relationship between single nucleotide polymorphisms (SNP) in candidate genes encoding DNA damage recognition/repair/response and steroid metabolism proteins with respect to clinical radiation toxicity in a retrospective cohort of patients previously treated with three-dimensional conformal radiotherapy (3-DCRT) for prostate cancer.

Experimental Design: One hundred twenty-four patients with prostate cancer underwent 3-DCRT at our institution between September 1996 and December 2000. Of these, 83 consented for follow-up of blood sampling and SNP analysis. Twenty-eight patients were documented as having experienced grade ≥2 late bladder or rectal toxicity (scoring system of Radiation Therapy Oncology Group) on at least one follow-up visit. We analyzed 49 SNPs in BRCA1, BRCA2, ESR1, XRCC1, XRCC2, XRCC3, NBN, RAD51, RAD52, LIG4, ATM, BCL2, TGFB1, MSH6, ERCC2, XPF, NR3C1, CYP1A1, CYP2C9, CYP2C19, CYP3A5, CYP2D6, CYP11B2, and CYP17A1 genes using the Pyrosequencing technique.

Results: Significant univariate associations with late rectal or bladder toxicity (grade ≥2) were found for XRCC3 (A>G 5′ untranslated region NT 4541), LIG4 (T>C Asp568Asp), MLH1 (C>T, Val219Ile), CYP2D6*4 (G>A splicing defect), mean rectal and bladder dose, dose to 30% of rectum or bladder, and age <60 years. On Cox multivariate analysis, significant associations with toxicity were found for LIG4 (T>C, Asp568Asp), ERCC2 (G>A, Asp711Asp), CYP2D6*4 (G>A, splicing defect), mean bladder dose >60 Gy, and dose to 30% of rectal volume >75 Gy.

Conclusions: In this study, we identified SNPs in LIG4, ERCC2, and CYP2D6 genes as putative markers to predict individuals at risk for complications arising from radiation therapy in prostate cancer.
Metformin Inhibits Cytokine-Induced Nuclear Factor κB Activation Via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells
Authors: Hattori Yoshiyuki , Suzuki Kunihiro , Hattori Sachiko , Kasai Kikuo
Published: April 2006

AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in regulation of energy homeostasis and metabolic stress. Metformin has been shown to activate AMPK. We hypothesized that metformin may prevent nuclear factor κB (NF-κB) activation in endothelial cells exposed to inflammatory cytokines. Metformin was observed to activate AMPK, as well as its downstream target, phosphoacetyl coenzyme A carboxylase, in human umbilical vein endothelial cells (HUVECs). Metformin also dose-dependently inhibited tumor necrosis factor (TNF)-α–induced NF-κB activation and TNF-α–induced IκB kinase activity. Furthermore, metformin attenuated the TNF-α–induced gene expression of various proinflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1, in HUVECs. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR), dose-dependently inhibited TNF-α- and interleukin-1β–induced NF-κB reporter gene expression. AICAR also suppressed the TNF-α- and interleukin-1β–induced gene expression of vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 in HUVECs. The small interfering RNA for AMPKα1 attenuated metformin or AICAR–induced inhibition of NF-κB activation by TNF-α, suggesting a possible role of AMPK in the regulation of cell inflammation. In light of these findings, we suggest that metformin attenuates the cytokine-induced expression of proinflammatory and adhesion molecule genes by inhibiting NF-κB activation via AMPK activation. Thus, it might be useful to target AMPK signaling in future efforts to prevent atherogenic and inflammatory vascular disease.
Long-Term Administration of Rho-Kinase Inhibitor Ameliorates Renal Damage in Malignant Hypertensive Rats
Authors: Ishikawa Yayoi , Nishikimi Toshio , Akimoto Kazumi , Ishimura Kimihiko , Ono Hidehiko , Matsuoka Hiroaki
Published: April 2006

We have shown recently that fasudil, a Rho-kinase inhibitor, has renoprotective effects in salt-sensitive hypertensive rats. We hypothesized that activation of Rho-kinase is involved in the pathogenesis of glomerulosclerosis in malignant hypertensive rats. To test this hypothesis, we studied the following 4 groups: control Wistar–Kyoto rats, untreated deoxycorticosterone-acetate salt spontaneously hypertensive rats (DOCA-SHR), low-dose fasudil-treated DOCA-SHR, and high-dose fasudil-treated DOCA-SHR. After 3 weeks of treatment, the effects of fasudil were examined. DOCA-SHR was characterized by increased blood pressure (BP); increased kidney weight; decreased renal function; increased proteinuria; abnormal histological findings; increased monocyte/macrophage infiltration; increased urinary 8-isoprostran levels; increased gene expression of collagen I, collagen III, transforming growth factor-β, and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits (p40phox, p47phox, and p67phox); and decreased gene expression of endothelial NO synthase (eNOS) in the renal cortex as compared with Wistar–Kyoto rats. Long-term high-dose fasudil treatment significantly improved renal function and histological findings without changing BP, as compared with untreated DOCA-SHR. Interestingly, long-term fasudil treatment significantly decreased monocyte/macrophage infiltration and urinary 8-isoprostran excretion, in association with decreased mRNA levels of transforming growth factor-β, collagen I, collagen III, and NADPH oxidase subunits (p40phox, p47phox, and p67phox), and increased mRNA levels of eNOS in the renal cortex. Long-term low-dose fasudil treatment tended to improve these variables slightly but did not affect most of them significantly. Our results suggest that long-term fasudil treatment provides renoprotective effects independent of BP-lowering activity. These renoprotective effects are associated with inhibition of extracellular matrix gene expression, monocyte/macrophage infiltration, oxidative stress, and upregulation of eNOS gene expression.
Heart Failure During Cardiac Pacing
Authors: Sweeney Michael O. , Hellkamp Anne S.
Published: April 2006

Background—

Right ventricular apical (RVA) pacing creates abnormal left ventricular contraction, hypertrophy, and reduced pump function. The adverse effects of ventricular desynchronization may explain the association of RVA pacing with an increased risk of heart failure hospitalization (HFH) in clinical trials.

Methods and Results—

Baseline and postimplantation variables were used to predict HFH in the Mode Selection Trial, a 2010-patient, 6-year trial of dual-chamber (DDDR) versus ventricular (VVIR) pacing in sinus node dysfunction. A Cox model showed that New York Heart Association (NYHA) class at baseline and follow-up predicted HFH (hazard ratio [HR], 3.99; 95% confidence interval [CI], 2.74–5.79 for NYHA class III/IV and HR, 2.17; 95% CI, 1.54–3.04 for NYHA class II versus class I); other predictors were heart failure (HR, 2.30; 95% CI, 1.70–3.11), atrioventricular (AV) block (HR, 1.48; 95% CI, 1.11–1.97), and myocardial infarction (MI)(HR, 1.37; 95% CI, 1.00–1.86). Postimplantation predictors were VVIR cumulative percent ventricular pacing (Cum%VP) >80 (HR, 3.58; 95% CI, 1.72–7.45), DDDR Cum%VP >40 or VVIR Cum%VP ≤80 (HR, 1.81; 95% CI, 0.94–3.50) versus DDDR Cum%VP ≤40; whether QRS duration (QRSd) was paced or spontaneous (HR, 2.21; 95% CI, 1.39–3.54; spontaneous versus paced); and drugs for atrial fibrillation (HR, 1.60; 95% CI, 1.19–2.15). Low baseline ejection fraction (EF) and postimplantation RVA-paced or spontaneous QRSd predicted HFH; the increased risk with QRSd was steeper for normal versus low EF (HR, 1.18; 95% CI, 1.11–1.27; versus HR, 1.08; 95% CI, 1.01–1.15; for a 10-ms increase); at a QRSd of ≈200 ms, normal- and low-EF patients had equivalent risk. HFH risk nearly doubled when VVIR Cum%VP was ≤80 or DDDR Cum%VP was >40 versus DDDR Cum%VP ≤40 and was additive with other risk factors.

Conclusions—

Differences in HFH risk can be explained by interactions between substrate (atrial fibrillation, AV conduction, heart failure, MI, EF) and pacing promoters (ventricular desynchronization-paced QRSd and Cum%VP, and AV desynchronization-pacing mode). Management of RVA pacing is important for reducing the risk of HFH, particularly among patients with low EF and heart failure.
Discrepancies between Different Northern Hemisphere Summer Atmospheric Data Products
Authors: Greatbatch Richard J. , Rong Ping-ping
Published: April 2006

Northern Hemisphere summer (July–August) data from the NCEP–NCAR and ECMWF 40-yr Re-Analysis (ERA-40) reanalyses are compared with each other and with Trenberth's sea level pressure (SLP) dataset. Discrepancies in SLP and 500 hPa are mostly confined to a band connecting North Africa and Asia. In the NCEP–NCAR reanalysis, there is a negative offset in SLP over North Africa and Asia prior to the late 1960s, together with a similar problem in 500-hPa height, and in Trenberth's data there is a negative offset in SLP over Asia prior to the early 1990s. Both these offsets magnify the linear trend from 1958 to 2002 over North Africa and Asia in the NCEP–NCAR and Trenberth datasets. On the other hand, the interannual variability in the three datasets is highly correlated during the periods between these offsets. Compared to SLP and 500-hPa height, there is a more extensive area of discrepancy in 2-m temperature that extends eastward from North Africa across the subtropics into the Pacific, with an additional area of discrepancy over the Arctic and parts of the American continent. At 500 and 100 hPa, the biggest differences in the temperature time series are found in the Tropics, with a marked jump being evident in the late 1970s in the NCEP–NCAR, but not in the ERA-40, reanalysis that is almost certainly associated with the introduction of satellite data. On the other hand, all three datasets agree well over Europe. The summer North Atlantic Oscillation (NAO), defined here as the first EOF of summer mean SLP over the Euro-Atlantic sector, agrees well between the different datasets. The results indicate that the upward trend in the summer index in the 1960s is part of a longer-period interdecadal cycle, with relatively high index values also being found during the 1930s. The running cross correlation between the central England temperature record and the summer NAO shows a strong correlation throughout the last half of the twentieth century, but much reduced correlation in the early part of the twentieth century. It is not clear whether the change in correlation is real, or a data artifact, a topic that requires further research.
A Description of Interdecadal Time-Scale Propagating North Atlantic Sea Surface Temperature Anomalies and Their Effect on Winter European Climate, 1948–2002
Authors: Sinha Bablu , Topliss Brenda
Published: April 2006

Eastward-propagating interdecadal time-scale sea surface temperature (SST) winter anomalies have been shown to exist at the North Atlantic subpolar/subtropical gyre boundary. Heat flux and surface air temperature signatures of these anomalies are investigated using satellite- and ship-based SST observations and atmospheric reanalysis. Using bandpass filter analysis, retaining periods between 9 and 25 yr, a succession of coherent propagating SST anomalies is identified. The size, speed, propagation path, and decay characteristics of propagating anomalies detected during the period 1948–2002 are documented. The behavior of the propagations changes between the periods 1948–70 and 1970–2002. In the former period, SST anomalies propagated from the east coast of North America to the British Isles in ∼10 yr. The anomalies displayed a well-defined life cycle, growing in the western basin (west of 40°W) and decaying in the eastern basin. During the period 1970–2002, SST anomalies did not propagate deep into the eastern basin, but grew in the western basin and then ceased propagating. Oceanic anomalies have a comparable marked signature in surface sensible and latent heat fluxes and in surface air temperature. Winter surface heat flux anomalies act to amplify SST anomalies during the middle of their lifetimes, normally in the west-central Atlantic. At other times, heat flux anomalies are associated with decay of anomalies. Surface heat fluxes do not always act to cause propagation, and it is likely that other processes such as advection play a role in the propagation mechanism. North European winter surface air temperatures are raised or lowered by up to ±0.5°C over decadal time scales (∼1/3 of the total variation over the United Kingdom) when an SST anomaly reaches the eastern boundary. A variety of processes can cause SST variation on decadal time scales at the eastern boundary, but in the 1950s and 1960s the variability at these periods was the signature of features that had propagated across the Atlantic from the North American coast.
The New Hadley Centre Climate Model (HadGEM1): Evaluation of Coupled Simulations
Authors: Johns T. C. , Durman C. F. , Banks H. T. , Roberts M. J. , McLaren A. J. , Ridley J. K. , Senior C. A. , Williams K. D. , Jones A. , Rickard G. J. , Cusack S. , Ingram W. J. , Crucifix M. , Sexton D. M. H. , Joshi M. M. , Dong B.-W. , Spencer H. , Hill R. S. R. , Gregory J. M. , Keen A. B. , Pardaens A. K. , Lowe J. A. , Bodas-Salcedo A. , Stark S. , Searl Y.
Published: April 2006

A new coupled general circulation climate model developed at the Met Office's Hadley Centre is presented, and aspects of its performance in climate simulations run for the Intergovernmental Panel on Climate Change Fourth Assessment Report (IPCC AR4) documented with reference to previous models. The Hadley Centre Global Environmental Model version 1 (HadGEM1) is built around a new atmospheric dynamical core; uses higher resolution than the previous Hadley Centre model, HadCM3; and contains several improvements in its formulation including interactive atmospheric aerosols (sulphate, black carbon, biomass burning, and sea salt) plus their direct and indirect effects. The ocean component also has higher resolution and incorporates a sea ice component more advanced than HadCM3 in terms of both dynamics and thermodynamics. HadGEM1 thus permits experiments including some interactive processes not feasible with HadCM3. The simulation of present-day mean climate in HadGEM1 is significantly better overall in comparison to HadCM3, although some deficiencies exist in the simulation of tropical climate and El Niño variability. We quantify the overall improvement using a quasi-objective climate index encompassing a range of atmospheric, oceanic, and sea ice variables. It arises partly from higher resolution but also from greater fidelity in modeling dynamical and physical processes, for example, in the representation of clouds and sea ice. HadGEM1 has a similar effective climate sensitivity (2.8 K) to a CO2 doubling as HadCM3 (3.1 K), although there are significant regional differences in their response patterns, especially in the Tropics. HadGEM1 is anticipated to be used as the basis both for higher-resolution and higher-complexity Earth System studies in the near future.
The Physical Properties of the Atmosphere in the New Hadley Centre Global Environmental Model (HadGEM1). Part II: Aspects of Variability and Regional Climate
Authors: Ringer M. A. , Martin G. M. , Greeves C. Z. , Hinton T. J. , James P. M. , Pope V. D. , Scaife A. A. , Stratton R. A. , Inness P. M. , Slingo J. M. , Yang G.-Y.
Published: April 2006

The performance of the atmospheric component of the new Hadley Centre Global Environmental Model (HadGEM1) is assessed in terms of its ability to represent a selection of key aspects of variability in the Tropics and extratropics. These include midlatitude storm tracks and blocking activity, synoptic variability over Europe, and the North Atlantic Oscillation together with tropical convection, the Madden–Julian oscillation, and the Asian summer monsoon.

Comparisons with the previous model, the Third Hadley Centre Coupled Ocean–Atmosphere GCM (HadCM3), demonstrate that there has been a considerable increase in the transient eddy kinetic energy (EKE), bringing HadGEM1 into closer agreement with current reanalyses. This increase in EKE results from the increased horizontal resolution and, in combination with the improved physical parameterizations, leads to improvements in the representation of Northern Hemisphere storm tracks and blocking. The simulation of synoptic weather regimes over Europe is also greatly improved compared to HadCM3, again due to both increased resolution and other model developments.

The variability of convection in the equatorial region is generally stronger and closer to observations than in HadCM3. There is, however, still limited convective variance coincident with several of the observed equatorial wave modes. Simulation of the Madden–Julian oscillation is improved in HadGEM1: both the activity and interannual variability are increased and the eastward propagation, although slower than observed, is much better simulated. While some aspects of the climatology of the Asian summer monsoon are improved in HadGEM1, the upper-level winds are too weak and the simulation of precipitation deteriorates. The dominant modes of monsoon interannual variability are similar in the two models, although in HadCM3 this is linked to SST forcing, while in HadGEM1 internal variability dominates.

Overall, analysis of the phenomena considered here indicates that HadGEM1 performs well and, in many important respects, improves upon HadCM3. Together with the improved representation of the mean climate, this improvement in the simulation of atmospheric variability suggests that HadGEM1 provides a sound basis for future studies of climate and climate change.
Examination of Convection-Allowing Configurations of the WRF Model for the Prediction of Severe Convective Weather: The SPC/NSSL Spring Program 2004
Authors: Kain John S. , Weiss S. J. , Levit J. J. , Baldwin M. E. , Bright D. R.
Published: April 2006

Convection-allowing configurations of the Weather Research and Forecast (WRF) model were evaluated during the 2004 Storm Prediction Center–National Severe Storms Laboratory Spring Program in a simulated severe weather forecasting environment. The utility of the WRF forecasts was assessed in two different ways. First, WRF output was used in the preparation of daily experimental human forecasts for severe weather. These forecasts were compared with corresponding predictions made without access to WRF data to provide a measure of the impact of the experimental data on the human decision-making process. Second, WRF output was compared directly with output from current operational forecast models. Results indicate that human forecasts showed a small, but measurable, improvement when forecasters had access to the high-resolution WRF output and, in the mean, the WRF output received higher ratings than the operational Eta Model on subjective performance measures related to convective initiation, evolution, and mode. The results suggest that convection-allowing models have the potential to provide a value-added benefit to the traditional guidance package used by severe weather forecasters.
Effect of Food, an Antacid, and the H2 Antagonist Ranitidine on the Absorption of BAY 59–7939 (Rivaroxaban), an Oral, Direct Factor Xa Inhibitor, in Healthy Subjects
Authors: Kubitza Dagmar , Becka Michael , Zuehlsdorf Michael , Mueck Wolfgang
Published: April 2006

To investigate the influence of food and administration of an antacid (aluminum‐magnesium hydroxide) or ranitidine on the absorption of BAY 59–7939 (rivaroxaban), 4 randomized studies were performed in healthy male subjects. In 2 food interaction studies, subjects received BAY 59–7939, either as two 5‐mg tablets (fasted and fed), four 5‐mg tablets (fasted), or one 20‐mg tablet (fasted and fed). In 2 drug interaction studies, BAY 59–7939 (six 5‐mg tablets) was given alone or with ranitidine (150 mg twice daily, preceded by a 3‐day pretreatment phase) or antacid (10 mL). Plasma samples were obtained to assess pharmacokinetic and pharmacodynamic parameters of BAY 59–7939. In the presence of food, time to maximum concentration (tmax) was delayed by 1.25 hours; maximum concentration (Cmax) and area under the curve (AUC) were increased, with reduced interindividual variability at higher doses of BAY 59–7939. Compared with baseline, BAY 59–7939 resulted in a relative increase in maximum prothrombin time (PT) prolongation of 44% (10 mg) and 53% (20 mg) in the fasted state, compared with 53% and 83% after food. Time to maximum PT prolongation was delayed by 0.5 to 1.5 hours after food, with no relevant influence of food type. No significant difference in Cmax and AUC was observed with coadministration of BAY 59–7939 and ranitidine or antacid.
Talar Dome Access for Osteochondral Lesions
Authors: Muir Dawson , Saltzman Charles L. , Tochigi Yuki , Amendola Ned
Published: April 2006

Background

Recently, osteochondral grafting has become a popular procedure for treating challenging talar dome lesions. However, no guidelines exist for selection of the surgical approach to obtain perpendicular access to the talar dome.

Hypothesis

The majority of the talar dome can be accessed for perpendicular resurfacing procedures without need for osteotomy.

Study Design

Descriptive laboratory study.

Methods

Nine human cadaveric ankles were dissected in a standard fashion to expose the talar dome. Seven approaches were used, including 4 arthrotomies (anteromedial, anterolateral, posteromedial, and posterolateral) and 3 osteotomies (anterolateral [Chaput], distal fibula, and medial malleolar). The area available for perpendicular access to the dome was determined for each approach.

Results

On average, 17% (range, 10%-24%) of the medial talar dome and 20% (range, 16%-25%) of the lateral talar dome could not be accessed without osteotomy. On the lateral aspect of the superior talar dome surface, an anterolateral osteotomy adds a mean of 22% to sagittal plane exposure. Malleolar osteotomies, when performed using the method described, provide access to the entire medial and lateral sides; however, there remains a mean residual 15% (range, 11%-38%) of the central talar dome that cannot be accessed in a perpendicular manner with any approach.

Conclusion

Most of the talar dome can be accessed perpendicularly for resurfacing without malleolar osteotomy. Osteotomies substantially increase the access and are needed for extensive lesions. Part of the central portion of the talar dome is inaccessible to perpendicular resurfacing techniques with any standard approach.

Clinical Relevance

This study generated clear clinical guidelines to help decision making regarding the surgical approach to resurface the talar dome with osteochondral techniques. The majority of the talar dome can be accessed without osteotomy.
Retrograde Drilling for Osteochondral Lesions of the Talar Dome
Authors: Kono Michihaya , Takao Masato , Naito Kohei , Uchio Yuji , Ochi Mitsuo
Published: April 2006

Background

For the treatment of osteochondral lesions of the talar dome without detachment of the cartilage, there is little information on whether transmalleolar drilling or retrograde drilling is more effective in terms of clinical and morphologic evaluations.

Hypothesis

Retrograde drilling may be more effective than transmalleolar drilling for lesions without cartilage detachment.

Study Design

Case control study; Level of evidence, 3.

Methods

Subjects were 30 patients with lesions on 1 foot of grade 0 or I, determined according to a modified Pritsch classification system. Nineteen patients underwent transmalleolar drilling (TMD group), and 11 patients underwent retrograde drilling (RD group). Ankle arthroscopy was performed 1 year postoperatively to evaluate cartilage conditions.

Results

Arthroscopic findings revealed that in the TMD group, 11 lesions (57.9%) were unchanged (grade I), and 8 lesions (42.1%) had deteriorated from grade 0 to I; in the RD group, 3 lesions (27.2%) had improved from grade I to 0, and 8 (72.8%) were unchanged (2 grade 0 lesions and 6 grade I lesions). There was a significant difference between the 2 groups in the distribution of cases that had improved, were unchanged, or had deteriorated (P < .0001).

Conclusions

This study showed that compared with transmalleolar drilling, retrograde drilling for osteochondral lesions of the talar dome can improve the arthroscopic assessment of the lesions.
Validating the Utility of the Spanish Version of the American Diabetes Association Risk Test
Authors: Long Janice , Rozo-Rivera Astrid , Akers Timothy , VanGeest Jonathan B. , Bairan Annette , Fogarty Kieran J. , Sowell Richard
Published: April 2006

The American Diabetes Association (ADA) Risk Test, often used for decisions to blood glucose screen or not, lacks studies reporting the reliability or validity for the Spanish version of the tool. The objective of this study is to further validate the utility of the Spanish version of the ADA's Risk Test for Latino Populations. A convenience sample of 316 Latinos participated in this study. A positive but weak statistical correlation was found between blood glucose and the Risk Test score (.138), suggesting low reliability and validity of the Spanish version of the instrument. Two internal consistency estimates of reliability techniques were computed for the Risk Test for diabetes scale items, indicating low reliability.
A52>A6>A601>A5250>A601>A516>A52
Authors: Walker Stephen
Published: April 2006

This article proposes to explore various aspects of the sublime as they might be encountered on a journey around that paradigmatic experience of sublime oxymoron, the ring road. In common with more conventional sublime objects, it can elude our perceptual and imaginative grasp while providing exhilarating transport. Although the arguments used to push through the construction of ring roads are usually made on highly rationalized grounds and according to the logic of a systematizing thought, and although acceptable behavior on the ring road is clearly set out in highway legislation and codes, it will be suggested here that ring roads might also provide an instance where the experience of our designed environment can open up to different readings, thus broadening the ways in which the ring road might figure both as a site of experience and in thought. Although the ring road is usually off-limits for any architectural discussion, it will be suggested below that an examination of this limit case can have some relevance for the ways in which the experience of more conventional architectural settings is accounted for.
A Space for the Trace
Authors: Hillis Ken
Published: April 2006

eBay the firm and eBay as a set of everyday cultural practices together arise at a time of material excess combined with an intensified exteriorization of memory processes onto digital media devices. Exchange and use values on eBay are negotiated through elaborate, at times sensational, narrative histories contextualizing the object's past, ambiguous images, and fetishized practices. Individuals may pay a premium for a sense of imagined experience “exchanged” through buyers and sellers and other browsers through these narratives prior to the actual sale of any object. The indexicality of eBay—the sense that one is able somehow to experience a trace of the object or, just as important, its seller through online media—works to suggest that authenticity is transferable, an exchange value available to the highest bidder. The growing belief that Web sites such as eBay constitute the equivalent of material space contributes to this perception.
The Dialectics of Design
Authors: Jenkins Barbara
Published: April 2006

The popularity of deconstructivist architecture around the world has invited controversy over the sensationalist design of these buildings. New urbanists, in particular, have criticized decon architecture as alienating and disorienting. From a historical perspective, this opposition between deconstructivists and new urbanists is the latest in a long line of debates over what constitutes “good design.” Using a political-economy approach based on the work of Karl Polanyi, this article examines a centuries-long dialectic in design ideology between those who seek to embed design in social mores and those who attempt to “disembed” it from oppressive discourses. This analysis shows that the dialectic of design movements is intimately connected to the development of capitalist markets.
Theories of Change in Therapeutic Work
Authors: Stacey Ralph
Published: April 2006

This article explores how theories of personal change differ from each other according to the assumptions made about the nature of the individual, the relationship between the person and the social, and the nature of causality. Three different concepts of the individual person are distinguished, namely, the autonomous, the expressivist, and the social individual. Each of these implies different relationships between the individual and the social, and different theories of causality. From the perspective of the autonomous individual, change in a person is a rational reordering of individual thought processes. The cause of any personal change is rational effort of the individual. Clinical psychology and psychoanalysis reflect this perspective. From the expressivist perspective, each individual has an inner urge to self-actualize which is the cause of change. Humanistic psychology is based on this view. From the perspective of social individuals, the individual is a cultural being, necessarily dependent on others, who only develops a mind in interaction with others. From this perspective, individual change cannot be separated from change in the groups to which an individual belongs.
How and Why Parents Change Their Attitudes to Prenatal Diagnosis
Authors: Götz Ilse , Götz Manfred
Published: April 2006

Parents who know they are carriers of a genetically transmitted disease because they gave birth to an affected child are being offered a number of reproductive options in a subsequent pregnancy. We describe the attitudes and motives of parents of children with cystic fibrosis (CF) who were initially determined to use prenatal testing but eventually refused it. Based on our observations and clinical impressions we built a model of change that entails a series of stages and depicts change as a process. This begins with the provision of comprehensive information and emotional support through health professionals (Stage 1). The parents then engage in intense confrontation with the impact of prenatal testing and are exposed to influences from many sides. The repeated comparing of the arguments results in uncertainty and distress (Stage 2). When pregnancy occurs a decision must be made and the process culminates in participating in a life-or-death decision. If the parents cannot cope with that responsibility then a change towards rejection of prenatal diagnosis is likely (Stage 3). This phenomenon seems to be the most decisive factor. A case vignette is used to illustrate this model which may be applicable to many individuals who face major and emotionally fraught decisions.
Connections with the land
Authors: Takano Takako
Published: April 2006

This article focuses on an Inuit elders' ‘land-skills training course’ to explore its meanings regarding the concept of connection with the land, with particular reference to transmitting knowledge. While it is said that Inuit have close relationships with nature, their present attempts to ‘bond’ young people with the land have not been extensively examined. The study revealed a dilemma in contemporary Inuit society concerning what they should know and how they should be, at a time when traditional modes of knowledge transmission among extended family members were not functioning well. The course rationale was to guide young people to ‘be and become an Inuk’, the core of this being establishing a connection to the land. The formal school system was perceived as not delivering what community members considered to be important. A proper relationship with the land is directly linked to sustainability, and the land-skills course was the Inuit's response to questions about a sustainable future.
A taste of ‘modernity’
Authors: Hsu Carolyn L.
Published: April 2006

What does working in a western restaurant mean to people in urban China? This article, based on ethnographic research at three western food places in the northeastern Chinese city of Harbin, argues that for Harbiners at the turn of the century, working in western restaurants was meaningful for two reasons. First, these workplaces were seen as connected to the global capitalist economy and the world of cosmopolitan consumerism, in contrast to the local, provincial, and backward. Second, these workplaces were seen as distinct, and indeed oppositional, to state socialist workplaces and to the socialist understanding of work where individual contribution was rewarded by state paternalism. People who worked in western food restaurants understood work through the concept of development – people should develop themselves by acquiring skills and experiences through work. In other words, for those who worked in western food places, jobs were something to be ‘consumed’ like courses in a self-designed training program for entrepreneurship.
Negotiating ethics in dementia care
Authors: Brannelly Tula
Published: April 2006

Providing care for people with dementia is often complex and ethically difficult, and is guided by the values of people with dementia and professional and lay carers. Each participant brings often different, and sometimes conflicting, perspectives, which contribute to the difficulty of negotiating suitable care. This research examined how participation and inclusion were facilitated by community psychiatric nurses and social workers to achieve care for people with dementia. Practice was observed to provide snapshots of interactions between people with dementia, practitioners and lay carers, and interviews with practitioners interrogated practice. The analytical framework used was Tronto's (1993) ‘integrity of care’, taken from the wider feminist political argument of an ethic of care (Gilligan, 1982). The adoption in practice of an ethic of care strengthens the opportunity for increased participation and inclusion and therefore aims to provide care that fits with the values and preferences of people with dementia and their carers. The research found that of 50 people with dementia, 10 were placed in permanent placements such as nursing homes and residential homes, some unwillingly. This article discusses what happens in care when the ethical elements of an ethic of care are practised, and when they are not.
Mcl-1L cleavage is involved in TRAIL-R1– and TRAIL-R2–mediated apoptosis induced by HGS-ETR1 and HGS-ETR2 human mAbs in myeloma cells
Authors: Menoret Emmanuelle , Gomez-Bougie Patricia , Geffroy-Luseau Alexandrine , Daniels Sylvanne , Moreau Philippe , Le Gouill Steven , Harousseau Jean-Luc , Bataille Regis , Amiot Martine , Pellat-Deceunynck Catherine
Published: April 2006

We evaluated the ability of 2 human mAbs directed against TRAILR1 (HGS-ETR1) and TRAILR2 (HGS-ETR2) to kill human myeloma cells. HGS-ETR1 and HGS-ETR2 mAbs killed 15 and 9 human myeloma cell lines (HMCLs; n = 22), respectively. IL-6, the major survival and growth factor for these HMCLs, did not prevent their killing. Killing induced by either HGS-ETR1 or HGS-ETR2 was correlated with the cleavage of Mcl-1L, a major molecule for myeloma survival. Mcl-1L cleavage and anti-TRAILR HMCL killing were dependent on caspase activation. Kinetic studies showed that Mcl-1L cleavage occurred very early (less than 1 hour) and became drastic once caspase 3 was activated. Our data showed that both the extrinsic (caspase 8, Bid) and the intrinsic (caspase 9) pathways are activated by anti–TRAIL mAb. Finally, we showed that the HGS-ETR1 and, to a lesser extent, the HGS-ETR2 mAbs were able to induce the killing of primary myeloma cells. Of note, HGS-ETR1 mAb was able to induce the death of medullary and extramedullary myeloma cells collected from patients at relapse. Taken together, our data clearly encourage clinical trials of anti–TRAILR1 mAb in multiple myeloma, especially for patients whose disease is in relapse, at the time of drug resistance.
Differential expression of selected histone modifier genes in human solid cancers
Authors: Özdağ Hilal , Teschendorff Andrew E , Ahmed Ahmed Ashour , Hyland Sarah J , Blenkiron Cherie , Bobrow Linda , Veerakumarasivam Abhi , Burtt Glynn , Subkhankulova Tanya , Arends Mark J , Collins V Peter , Bowtell David , Kouzarides Tony , Brenton James D , Caldas Carlos
Published: April 2006

Background

Post-translational modification of histones resulting in chromatin remodelling plays a key role in the regulation of gene expression. Here we report characteristic patterns of expression of 12 members of 3 classes of chromatin modifier genes in 6 different cancer types: histone acetyltransferases (HATs)-EP300, CREBBP, andPCAF; histone deacetylases (HDACs)-HDAC1, HDAC2, HDAC4, HDAC5, HDAC7A, andSIRT1; and histone methyltransferases (HMTs)-SUV39H1andSUV39H2. Expression of each gene in 225 samples (135 primary tumours, 47 cancer cell lines, and 43 normal tissues) was analysedby QRT-PCR, normalized with 8 housekeeping genes, and given as a ratio by comparison with a universal reference RNA.

Results

This involved a total of 13,000 PCR assays allowing for rigorous analysis by fitting a linear regression model to the data. Mutation analysis ofHDAC1, HDAC2, SUV39H1, andSUV39H2revealed only two out of 181 cancer samples (both cell lines) with significant coding-sequence alterations. Supervised analysis and Independent Component Analysis showed that expression of many of these genes was able to discriminate tumour samples from their normal counterparts. Clustering based on the normalized expression ratios of the 12 genes also showed that most samples were grouped according to tissue type. Using a linear discriminant classifier and internal cross-validation revealed that with as few as 5 of the 12 genes,SIRT1, CREBBP, HDAC7A, HDAC5andPCAF, most samples were correctly assigned.

Conclusion

The expression patterns of HATs, HDACs, and HMTs suggest these genes are important in neoplastic transformation and have characteristic patterns of expression depending on tissue of origin, with implications for potential clinical application.
Molecular characterization of Coxiella burnetii isolates by infrequent restriction site-PCR and MLVA typing
Authors: Arricau-Bouvery Nathalie , Hauck Yolande , Bejaoui Awatef , Frangoulidis Dimitrios , Bodier Christelle C , Souriau Armel , Meyer Hermann , Neubauer Heinrich , Rodolakis Annie , Vergnaud Gilles
Published: April 2006

Background

Coxiella burnetii, the causative agent of Q fever, has a wide host range. Few epidemiological tools are available, and they are often expensive or not easily standardized across laboratories. In this work,C. burnetiiisolates from livestock and ticks were typed using infrequent restriction site-PCR (IRS-PCR) and multiple loci variable number of tandem repeats (VNTR) analysis (MLVA).

Results

By applying IRS-PCR, 14C. burnetiiisolates could be divided into six groups containing up to five different isolates. Clustering as deduced from MLVA typing with 17 markers provided an increased resolution with an excellent agreement to IRS-PCR, and with the plasmid type of each strain. MLVA was then applied to 28 additionalC. burnetiiisolates of different origin and 36 different genotypes were identified among the 42 isolates investigated. The clustering obtained is in agreement with published Multiple Locus Sequence Typing (MLST) data. Two panels of markers are proposed, panel 1 which can be confidently typed on agarose gel at a lower cost and in any laboratory setting (10 minisatellite markers with a repeat unit larger than 9 bp), and panel 2 which comprises 7 microsatellites and provides a higher discriminatory power.

Conclusion

Our analyses demonstrate that MLVA is a powerful and promising molecular typing tool with a high resolution and of low costs. The consistency of the results with independent methods suggests that MLVA can be applied for epidemiological studies. The resulting data can be queried on a dedicated MLVA genotyping Web service.