bluuebunny/crossref_metadata_2025 huggingface dataset:
Endocytic response of type I alveolar epithelial cells to hypertonic stress
Authors: Wang Shaohua , Singh Raman Deep , Godin Lindsay , Pagano Richard E. , Hubmayr Rolf D.
Published: January 2011

We present plasma membrane (PM) internalization responses of type I alveolar epithelial cells to a 50 mosmol/l increase in tonicity. Our research is motivated by interest in ATI repair, for which endocytic retrieval of PM appears to be critical. We validated pharmacological and molecular tools to dissect the endocytic machinery of these cells and used these tools to test the hypothesis that osmotic stress triggers a pathway-specific internalization of PM domains. Validation experiments confirmed the fluorescent analogs of lactosyl-ceramide, transferrin, and dextran as pathway-specific cargo of caveolar, clathrin, and fluid-phase uptake, respectively. Pulse-chase experiments indicate that hypertonic exposure causes a downregulation of clathrin and fluid-phase endocytosis while stimulating caveolar endocytosis. The tonicity-mediated increase in caveolar endocytosis was associated with the translocation of caveolin-1 from the PM and was absent in cells that had been transfected with dominant-negative dynamin constructs. In separate experiments we show that hypertonic exposure increases the probability of PM wound repair following micropuncture from 82 ± 4 to 94 ± 2% ( P < 0.01) and that this effect depends on Src pathway activation-mediated caveolar endocytosis. The therapeutic and biological implications of our findings are discussed.
An EGFR–Src–Arg–Cortactin Pathway Mediates Functional Maturation of Invadopodia and Breast Cancer Cell Invasion
Authors: Mader Christopher C. , Oser Matthew , Magalhaes Marco A. O. , Bravo-Cordero Jose Javier , Condeelis John , Koleske Anthony J. , Gil-Henn Hava
Published: January 2011

Invasive carcinoma cells use specialized actin polymerization–driven protrusions called invadopodia to degrade and possibly invade through the extracellular matrix (ECM) during metastasis. Phosphorylation of the invadopodium protein cortactin is a master switch that activates invadopodium maturation and function. Cortactin was originally identified as a hyperphosphorylated protein in v-Src–transformed cells, but the kinase or kinases that are directly responsible for cortactin phosphorylation in invadopodia remain unknown. In this study, we provide evidence that the Abl-related nonreceptor tyrosine kinase Arg mediates epidermal growth factor (EGF)–induced cortactin phosphorylation, triggering actin polymerization in invadopodia, ECM degradation, and matrix proteolysis–dependent tumor cell invasion. Both Src and Arg localize to invadopodia and are required for EGF-induced actin polymerization. Notably, Arg overexpression in Src knockdown cells can partially rescue actin polymerization in invadopodia while Src overexpression cannot compensate for loss of Arg, arguing that Src indirectly regulates invadopodium maturation through Arg activation. Our findings suggest a novel mechanism by which an EGFR–Src–Arg–cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Furthermore, they identify Arg as a novel mediator of invadopodia function and a candidate therapeutic target to inhibit tumor invasion in vivo. Cancer Res; 71(5); 1730–41. ©2011 AACR.
Oncogenic Synergism between ErbB1, Nucleolin, and Mutant Ras
Authors: Farin Keren , Schokoroy Sari , Haklai Roni , Cohen-Or Ifat , Elad-Sfadia Galit , Reyes-Reyes Merit E. , Bates Paula J. , Cox Adrienne D. , Kloog Yoel , Pinkas-Kramarski Ronit
Published: January 2011

Alterations in the ErbB family of growth factor receptors, their signaling components, and mutational activation of Ras proteins are major contributors to malignant transformation. Recently, mutant Ras was shown to be capable of activating ErbB receptors in a ligand-independent manner. Furthermore, it was observed that nucleolin, a transcriptional regulator and ribosome biogenesis factor, can bind both K-Ras and the cytoplasmic tail of ErbB receptors to enhance ErbB receptor activation. However, the functional significance of these interactions to cancer pathogenesis has not been probed. Here, we show that endogenous nucleolin interacts simultaneously in vivo with endogenous Ras and ErbB1 (EGFR) in cancer cells. The C-terminal 212 amino acids of nucleolin were determined to be sufficient to interact with ErbB1 and all Ras protein isoforms (H-, N-, and K-Ras). Nucleolin partially colocalizes with Ras at the plasma membrane. Moreover, activated but not wild-type Ras facilitates nucleolin interaction with ErbB1 and stabilizes ErbB1 receptor levels. Most importantly, these three oncogenes synergistically facilitate anchorage-independent cell growth in vitro and tumor growth in vivo. Our findings suggest strategies to target nucleolin as a general approach to inhibiting ErbB- and Ras-driven cancers. Cancer Res; 71(6); 2140–51. ©2011 AACR.
18FDG-PET Predicts Pharmacodynamic Response to OSI-906, a Dual IGF-1R/IR Inhibitor, in Preclinical Mouse Models of Lung Cancer
Authors: McKinley Eliot T. , Bugaj Joseph E. , Zhao Ping , Guleryuz Saffet , Mantis Christine , Gokhale Prafulla C. , Wild Robert , Manning H. Charles
Published: January 2011

Purpose: To evaluate 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography imaging (18FDG-PET) as a predictive, noninvasive, pharmacodynamic (PD) biomarker of response following administration of a small-molecule insulin-like growth factor-1 receptor and insulin receptor (IGF-1R/IR) inhibitor, OSI-906.

Experimental Design: In vitro uptake studies of 3H-2-deoxy glucose following OSI-906 exposure were conducted evaluating correlation of dose with inhibition of IGF-1R/IR as well as markers of downstream pathways and glucose metabolism. Similarly, in vivo PD effects were evaluated in human tumor cell line xenografts propagated in athymic nude mice by 18FDG-PET at 2, 4, and 24 hours following a single treatment of OSI-906 for the correlation of inhibition of receptor targets and downstream markers.

Results: Uptake of 3H-2-deoxy glucose and 18FDG was significantly diminished following OSI-906 exposure in sensitive tumor cells and subcutaneous xenografts (NCI-H292) but not in an insensitive model lacking IGF-1R expression (NCI-H441). Diminished PD 18FDG-PET, collected immediately following the initial treatment agreed with inhibition of pIGF-1R/pIR, reduced PI3K (phosphoinositide 3-kinase) and MAPK (mitogen activated protein kinase) pathway activity, and predicted tumor growth arrest as measured by high-resolution ultrasound imaging.

Conclusion: 18FDG-PET seems to serve as a rapid, noninvasive PD marker of IGF-1R/IR inhibition following a single dose of OSI-906 and should be explored clinically as a predictive clinical biomarker in patients undergoing IGF-1R/IR–directed cancer therapy. Clin Cancer Res; 17(10); 3332–40. ©2011 AACR.
A Phase I Clinical Trial of Safingol in Combination with Cisplatin in Advanced Solid Tumors
Authors: Dickson Mark A. , Carvajal Richard D. , Merrill Alfred H , Gonen Mithat , Cane Lauren M. , Schwartz Gary K.
Published: January 2011

Purpose: Sphingosine 1-phosphate (S1P) is an important mediator of cancer cell growth and proliferation. Production of S1P is catalyzed by sphingosine kinase 1 (SphK). Safingol, (l-threo-dihydrosphingosine) is a putative inhibitor of SphK. We conducted a phase I trial of safingol (S) alone and in combination with cisplatin (C).

Experimental Design: A 3 + 3 dose escalation was used. For safety, S was given alone 1 week before the combination. S + C were then administered every 3 weeks. S was given over 60 to 120 minutes, depending on dose. Sixty minutes later, C was given over 60 minutes. The C dose of 75 mg/m2 was reduced in cohort 4 to 60 mg/m2 due to excessive fatigue.

Results: Forty-three patients were treated, 41 were evaluable for toxicity, and 37 for response. The maximum tolerated dose (MTD) was S 840 mg/m2 over 120 minutes C 60 mg/m2, every 3 weeks. Dose-limiting toxicity (DLT) attributed to cisplatin included fatigue and hyponatremia. DLT from S was hepatic enzyme elevation. S pharmacokinetic parameters were linear throughout the dose range with no significant interaction with C. Patients treated at or near the MTD achieved S levels of more than 20 μmol/L and maintained levels greater than and equal to 5 μmol/L for 4 hours. The best response was stable disease in 6 patients for on average 3.3 months (range 1.8–7.2 m). One patient with adrenal cortical cancer had significant regression of liver and lung metastases and another had prolonged stable disease. S was associated with a dose-dependent reduction in S1P in plasma.

Conclusions: Safingol, the first putative SphK inhibitor to enter clinical trials, can be safely administered in combination with cisplatin. Reversible dose-dependent hepatic toxicity was seen, as expected from preclinical data. Target inhibition was achieved with downregulation of S1P. The recommended phase II dose is S 840 mg/m2 and C 60 mg/m2, every 3 weeks. Clin Cancer Res; 17(8); 2484–92. ©2011 AACR.
SST0001, a Chemically Modified Heparin, Inhibits Myeloma Growth and Angiogenesis via Disruption of the Heparanase/Syndecan-1 Axis
Authors: Ritchie Joseph P. , Ramani Vishnu C. , Ren Yongsheng , Naggi Annamaria , Torri Giangiacomo , Casu Benito , Penco Sergio , Pisano Claudio , Carminati Paolo , Tortoreto Monica , Zunino Franco , Vlodavsky Israel , Sanderson Ralph D. , Yang Yang
Published: January 2011

Purpose: Heparanase promotes myeloma growth, dissemination, and angiogenesis through modulation of the tumor microenvironment, thus highlighting the potential of therapeutically targeting this enzyme. SST0001, a nonanticoagulant heparin with antiheparanase activity, was examined for its inhibition of myeloma tumor growth in vivo and for its mechanism of action.

Experimental Design: The ability of SST0001 to inhibit growth of myeloma tumors was assessed using multiple animal models and a diverse panel of human and murine myeloma cell lines. To investigate the mechanism of action of SST0001, pharmacodynamic markers of angiogenesis, heparanase activity, and pathways downstream of heparanase were monitored. The potential use of SST0001 as part of a combination therapy was also evaluated in vivo.

Results: SST0001 effectively inhibited myeloma growth in vivo, even when confronted with an aggressively growing tumor within human bone. In addition, SST0001 treatment causes changes within tumors consistent with the compound's ability to inhibit heparanase, including downregulation of HGF, VEGF, and MMP-9 expression and suppressed angiogenesis. SST0001 also diminishes heparanase-induced shedding of syndecan-1, a heparan sulfate proteoglycan known to be a potent promoter of myeloma growth. SST0001 inhibited the heparanase-mediated degradation of syndecan-1 heparan sulfate chains, thus confirming the antiheparanase activity of this compound. In combination with dexamethasone, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment.

Conclusions: These results provide mechanistic insight into the antitumor action of SST0001 and validate its use as a novel therapeutic tool for treating multiple myeloma. Clin Cancer Res; 17(6); 1382–93. ©2011 AACR.
Pentraxin-3 Is a Novel Biomarker of Lung Carcinoma
Authors: Diamandis Eleftherios P. , Goodglick Lee , Planque Chris , Thornquist Mark D.
Published: January 2011

Purpose: Our objective was to validate the performance of three new candidate lung cancer biomarkers, pentraxin-3 (PTX3), human kallikrein 11 (KLK11), and progranulin.

Experimental Design: We analyzed by commercial ELISA, and with a blinded protocol, 422 samples from 203 patients with lung carcinoma, 180 individuals with high risk for lung cancer (heavy smokers), and 43 individuals with cancers other than lung. All samples were obtained from the Early Detection Research Network (Reference set A).

Results: We found that progranulin and KLK11 were not informative lung cancer biomarkers, with areas under the receiver operating characteristic curve (AUC; ROC), close to 0.50. However, PTX3 was an informative lung cancer biomarker, with considerable ability to separate lung cancer patients from high-risk controls. At 90% and 80% specificity, the sensitivities versus the high-risk control group were 37% and 48%, respectively. The discriminatory ability of PTX3 was about the same with all major subtypes and histotypes of lung cancer. The AUC of the ROC curves increased according to the disease stage, from 0.64 (stage I) to 0.72 (stage IV).

Conclusion: PTX3, but not KLK11 or progranulin, is a new serum biomarker for lung carcinoma. Its diagnostic sensitivity and specificity is similar to other clinically used lung cancer biomarkers. More studies are needed to establish if PTX3 has clinical utility for lung cancer diagnosis and management. Clin Cancer Res; 17(8); 2395–9. ©2011 AACR.
Mouse Snail Is a Target Gene for HIF
Authors: Luo Daochun , Wang Jinxia , Li Jeff , Post Martin
Published: January 2011

The transcriptional inhibitor Snail is a critical regulator for epithelial–mesenchymal transition (EMT). Although low oxygen induces Snail transcription, thereby stimulating EMT, a direct role of hypoxia-inducible factor (HIF) in this process remains to be demonstrated. Here we show that hypoxia induces the expression of Snail via HIF. In silico analysis identified a potential hypoxia-response element (HRE) close to the minimal promoter of the human and mouse genome of the snail gene. Gel shift assays demonstrated that a specific hypoxia-inducible complex is formed with the putative HRE and that the complex contains HIF proteins. ChIP assays confirmed the interaction of HIF proteins with the putative HRE in vivo. Reporter gene analyses showed that the putative HRE responds to hypoxia in its natural position as well as in front of a heterologous promoter and that the HRE is directly activated by HIF-1α or HIF-2α. HIF knockdown with siRNA at 2% oxygen and overexpression of an oxygen-insensitive HIF (HIF-ΔODD) mutant at 21% oxygen showed that HIF regulates Snail activation and subsequent cell migration. Our findings identify snail as a HIF target gene and provide novel insights into the regulation of snail and hypoxia-induced EMT. Mol Cancer Res; 9(2); 234–45. ©2011 AACR.
An Image-Based, High-Throughput Screening Assay for Molecules that Induce Excess DNA Replication in Human Cancer Cells
Authors: Zhu Wenge , Lee Chrissie Y. , Johnson Ronald L. , Wichterman Jennifer , Huang Ruili , DePamphilis Melvin L.
Published: January 2011

Previous studies have shown DNA re-replication can be induced in cells derived from human cancers under conditions in which it is not possible for cells derived from normal tissues. Because DNA re-replication induces cell death, this strategy could be applied to the discovery of potential anticancer therapeutics. Therefore, an imaging assay amenable to high-throughput screening was developed that measures DNA replication in excess of four genomic equivalents in the nuclei of intact cells and indexes cell proliferation. This assay was validated by screening a library of 1,280 bioactive molecules on both normal and tumor-derived cells where it proved more sensitive than current methods for detecting excess DNA replication. This screen identified known inducers of excess DNA replication, such as inhibitors of microtubule dynamics, and novel compounds that induced excess DNA replication in both normal and cancer cells. In addition, two compounds were identified that induced excess DNA replication selectively in cancer cells and one that induced endocycles selectively in cancer cells. Thus, this assay provides a new approach to the discovery of compounds useful for investigating the regulation of genome duplication and for the treatment of cancer. Mol Cancer Res; 9(3); 294–310. ©2011 AACR.
Effect of Chronic and Intermittent Calorie Restriction on Serum Adiponectin and Leptin and Mammary Tumorigenesis
Authors: Rogozina Olga P. , Bonorden Melissa J.L. , Seppanen Christine N. , Grande Joseph P. , Cleary Margot P.
Published: January 2011

The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels was investigated in relation to mammary tumorigenesis. 10-wks old MMTV-TGF-α female mice were assigned to ad libitum fed (AL; AIN-93M diet), ICR (3-week 50% caloric restriction, AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3-wks 100% AL consumption of AIN-93M), and CCR (calorie and nutrient intake matched for each 6-wks ICR cycle, ∼75% of AL) groups. Mice were sacrificed at 79 (end of restriction) or 82 (end of refeeding) wks of age. Serum was obtained in cycles 1, 3, 5, 8, 11, and terminal. Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad. Although we did not show an association of either adiponectin or leptin with individual mice in relation to mammary tumorigenesis, we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction. Cancer Prev Res; 4(4); 568–81. ©2011 AACR.
Enlargement of Catheter Ablation Lesions in Infant Hearts With Cryothermal Versus Radiofrequency Energy
Authors: Khairy Paul , Guerra Peter G. , Rivard Lena , Tanguay Jean-François , Landry Evelyn , Guertin Marie-Claude , Macle Laurent , Thibault Bernard , Tardif Jean-Claude , Talajic Mario , Roy Denis , Dubuc Marc
Published: January 2011

Background—

Radiofrequency catheter ablation in immature hearts has been associated with marked enlargement of lesions over time, with potential for related late adverse events. It remains unknown whether cryothermal ablation lesions display a similar pattern of growth.

Methods and Results—

Ablation lesions (n=384) were performed in 32 infant miniature swine in right and left atria, ventricles, and atrioventricular (AV) grooves preselected by a randomized factorial design devised to compare radiofrequency and cryothermal lesions produced by 7F 4-mm electrode-tip catheters. Animals were euthanized acutely or at 1, 6, or 12 months, according to the randomization scheme. The miniature swine weighed 8.8±1.2 kg and were 63±13 days of age at time of ablation. The minimum temperature during cryoablation was −79.8±3.4°C and the average temperature during radiofrequency ablation was 54.4±5.5°C. On morphometric analyses, no differences in the rate of growth of ablation lesions were noted between the 2 energy modalities in atria (
P
=0.44), ventricles (
P
=0.57), or AV grooves (
P
=0.69). Lesion volumes increased 3.3-fold in atria (95% confidence interval [CI], 2.3 to 4.3;
P
=0.001) and 2.2-fold in ventricles (95% CI, 1.4 to 3.0;
P
<0.0001), with the difference between chambers being nonsignificant (
P
=0.22). Whereas the depth of AV groove lesions increased over time (1.9-fold; 95% CI, 1.5 to 2.3;
P
<0.0001), lesion volumes did not enlarge significantly (1.5-fold; 95% CI, 0.4 to 2.6;
P
=0.45).

Conclusions—

Ablation lesions produced by cryothermal energy in immature atrial and ventricular myocardium enlarge to a similar extent to radiofrequency ablation. In contrast, AV groove lesion volumes do not increase significantly with either energy modality.
Associations of Retinal Microvascular Signs and Intracranial Large Artery Disease
Authors: De Silva Deidre A. , Manzano Jennifer J.F. , Woon Fung-Peng , Liu Erica Yang , Lee Moi-Pin , Gan Hui-Yee , Chen Christopher P.L.H. , Chang Hui-Meng , Mitchell Paul , Wang Jie Jin , Lindley Richard I. , Wong Tien-Yin , Wong Meng-Cheong
Published: January 2011

Background and Purpose—

Intracranial large artery disease (ICLAD) is a major cause of ischemic stroke. Retinal microvascular changes are associated with stroke, including small vessel cerebral disease and extracranial carotid disease. We examined the relationship between ICLAD and retinal microvascular changes.

Methods—

This is a prospective cohort of 802 acute ischemic stroke patients. Retinal changes were assessed from photographs by graders masked to clinical data. ICLAD was evaluated using prespecified criteria.

Results—

ICLAD was not associated with ipsilateral retinal arteriolar/venular caliber, focal arteriolar narrowing, or arteriovenous nicking. Severe enhanced arteriolar light reflex was independently associated with any ICLAD (
P
=0.006) and severe ICLAD (
P
<0.001).

Conclusion—

Enhanced arteriolar light reflex, but not retinal vessel caliber, was related to ICLAD. These data suggest that retinal microvascular signs have specific associations with large cerebral vessel disease.
A Candidate Gene Study Revealed Sex-Specific Association Between the
OLR1
Gene and Carotid Plaque
Authors: Wang Liyong , Yanuck Danielle , Beecham Ashley , Gardener Hannah , Slifer Susan , Blanton Susan H. , Sacco Ralph L. , Rundek Tatjana
Published: January 2011

Background and Purpose—

Sex differences have been recognized in stroke risk; however, the sex-dependent genetic contribution to stroke is unclear. We sought to examine the sex-dependent associations between genes involved in lipid metabolism and carotid atherosclerotic plaque, a subclinical precursor of stroke.

Methods—

For the Genetic Determinant of Subclinical Carotid Disease study, 287 Dominicans ascertained through the Northern Manhattan Study were examined for carotid plaque using high-resolution ultrasound. Sixty-four single nucleotide polymorphisms (SNPs) in 11 lipid-related genes were genotyped. Plaque presence and plaque subphenotypes, including multiple, thick, irregular, and calcified plaque, were analyzed. First, the interaction between each SNP and sex was evaluated for association with each plaque phenotype using multiple logistic regression and controlling for age, smoking, and the main effects of sex and SNP. For SNPs with suggestive evidence for interaction with sex (
P
<0.1 for the interaction term), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and plaque phenotypes.

Results—

The most compelling finding is with the missense SNP rs11053646 (K167N) in the
OLR1
gene, which encodes lectin-like oxidized low-density lipoprotein receptor. Stratification analysis revealed a strong association between rs11053646 and all plaque phenotypes in women (OR, 2.44 to 5.86;
P
=0.0003 to 0.0081) but not in men (OR, 0.85 to 1.22;
P
=0.77 to 0.92).

Conclusions—

Genetic variation in genes involved in lipid metabolism may have sex-dependent effects on carotid plaque burden. Our findings provide a plausible biological basis underlying the sex difference in cardiovascular risk.
Selectin-Mediated Recruitment of Bone Marrow Stromal Cells in the Postischemic Cerebral Microvasculature
Authors: Yilmaz Gokhan , Vital Shantel , Yilmaz Cigdem Erkuran , Stokes Karen Y. , Alexander J. Steven , Granger D. Neil
Published: January 2011

Background and Purpose—

The therapeutic potential of bone marrow stromal cells (BMSCs) has been demonstrated in different models of stroke. Although it is well established that BMSCs selectively migrate to the site of brain injury, the mechanisms underlying this process are poorly understood. This study addresses the hypothesis that selectins mediate the recruitment of BMSCs into the postischemic cerebral microvasculature.

Methods—

Focal ischemic stroke was induced by middle cerebral artery occlusion and reperfusion. Cell recruitment was monitored using either fluorescent- or radiolabeled BMSCs detected by intravital microscopy or tissue radioactivity. Mice were treated with either a blocking antibody against P- or E-selectin or with the nonselective selectin antagonist, fucoidin. The role of CD44 in cell recruitment was evaluated using BMSCs from CD44 knockout mice.

Results—

Middle cerebral artery occlusion and reperfusion was associated with a significantly increased adhesion of BMSCs in cerebral venules compared with sham mice. Immunoneutralization of either E- or P-selectin blocked the middle cerebral artery occlusion and reperfusion-induced recruitment of adherent BMSCs. An attenuated recruitment response in the postischemic hemisphere was also noted after fucoidin treatment or administration of CD44-deficient BMSCs.

Conclusions—

Cerebral vascular endothelium assume a proadhesive phenotype after ischemic stroke that favors the recruitment of BMSCs, which use both P- and E-selectin to home into the infarct site. CD44 may serve as the critical ligand for selectin-mediated BMSC recruitment.
Pharmacological Deep Vein Thrombosis Prophylaxis Does Not Lead to Hematoma Expansion in Intracerebral Hemorrhage With Intraventricular Extension
Authors: Wu Tzu-Ching , Kasam Mallik , Harun Nusrat , Hallevi Hen , Bektas Hesna , Acosta Indrani , Misra Vivek , Barreto Andrew D. , Gonzales Nicole R. , Lopez George A. , Grotta James C. , Savitz Sean I.
Published: January 2011

Background and Purpose—

Patients with intracerebral hemorrhage (ICH) are at high risk for development of deep venous thrombosis. Current guidelines state that low-dose subcutaneous low molecular weight heparin or unfractionated heparin may be considered at 3 to 4 days from onset. However, insufficient data exist on hematoma volume in patients with ICH before and after pharmacological deep venous thrombosis prophylaxis, leaving physicians with uncertainty regarding the safety of this practice.

Methods—

We identified patients from our stroke registry (June 2003 to December 2007) who presented with ICH only or ICH+intraventricular hemorrhage and received either low molecular weight heparin subcutaneously or unfractionated heparin within 7 days of admission and had a repeat CT scan performed within 4 days of starting deep venous thrombosis prophylaxis. We calculated the change in hematoma volume from the admission and posttreatment CTs. Hematoma volume was calculated using the ABC/2 method and intraventricular hemorrhage volumes were calculated using a published method of hand drawn regions of interest.

Results—

We identified 73 patients with a mean age of 63 years and median National Institutes of Health Stroke Scale score 11.5. The mean baseline total hematoma volume was 25.8 mL±23.2 mL. There was an absolute change in hematoma volume from pre- and posttreatment CT of −4.3 mL±11.0 mL. Two patients developed hematoma growth. Repeat analysis of patients given pharmacological deep venous thrombosis prophylaxis within 2 or 4 days after ICH found no increase in hematoma size.

Conclusions—

Pharmacological deep venous thrombosis prophylaxis given subcutaneously in patients with ICH and/or intraventricular hemorrhage in the subacute period is generally not associated with hematoma growth.
Quantitative Analysis of Hemorrhage Volume for Predicting Delayed Cerebral Ischemia After Subarachnoid Hemorrhage
Authors: Ko Sang-Bae , Choi H. Alex , Carpenter Amanda Mary , Helbok Raimund , Schmidt J. Michael , Badjatia Neeraj , Claassen Jan , Connolly E. Sander , Mayer Stephan A. , Lee Kiwon
Published: January 2011

Background and Purpose—

Delayed cerebral ischemia (DCI) is an important complication after subarachnoid hemorrhage and appears to be associated with clot burden on CT. Quantification of hemorrhage on digitized images may be a more accurate method for predicting DCI than qualitative scales.

Methods—

Quantitative analysis of clot burden on CT was performed in 160 subarachnoid hemorrhage patients who were scanned within 24 hours from the symptom onset between June 25, 2005 and July 19, 2009. Cisternal plus intraventricular hemorrhage volumes (CIHV) were classified into quartiles to evaluate their association with DCI. DCI was defined as neurological deterioration or cerebral infarction, or both attributable to vasospasm.

Results—

DCI occurred in 25% of the patients included (age, 55.4±14.5; male, 36.3%). Compared to the lowest quartile of CIHV (<9.6 mL), the higher quartile (9.6 mL–16.5 mL, 16.5 mL–31.0 mL, and ≥31.0 mL) was associated with a greater risk of DCI (odds ratio, 2.6, 4.1, and 6.1, respectively;
P
=0.01). Receiver-operating characteristic curve analysis showed that quantitative CIHV performed equivalently to the modified Fisher scale. Patients who had DCI develop in a specific vascular territory had higher amounts of blood volume in the corresponding cisterns. Patients in the highest quartile of CIHV also had a higher risk of death or severe disability at 3 months (71%) compared to other groups (23%, 19%, and 40% for first, second, and third quartiles, respectively).

Conclusions—

CIHV is a reasonable predictor for DCI and 3-month functional outcome in subarachnoid hemorrhage patients.
The Rome Statute's Amendment on the Crime of Aggression: Negotiations at the Kampala Review Conference
Authors: Trahan Jennifer
Published: January 2011

This past June, in Kampala, Uganda, at the first Review Conference on the International Criminal Court, States Parties forged an historic agreement, amending the Rome Statute to define the crime of aggression, and agreeing on conditions for the exercise of jurisdiction. While the definition had been essentially agreed upon during years of earlier negotiations, delegations in Kampala had to grapple with a host of complex issues related to the exercise of jurisdiction. They resolved that jurisdiction will be triggered both through Security Council referrals, as well as State Party or Prosecutor referrals, and the related "filter" mechanisms to achieve this. This result represented a significant breakthrough that was pragmatic, designed to avoided potential conflict with the U.N. Charter, and designed to protect the Court's independence. The final agreement, however, also contained compromises, excluding the acts of Non-States Parties from jurisdiction, allowing States Parties to opt out of jurisdiction, and delaying the exercise of jurisdiction until at least 2017.
Representing the "General Interests of the Defence": Boon or Bane? – A Stocktaking of the System of ad hoc Counsel at the ICC
Authors: Dieckmann Jens , Kerll Christina
Published: January 2011

This article seeks to assess the impact of the system of ad hoc counsel on the fairness of proceedings before the International Criminal Court. The authors begin by outlining the legal framework governing the appointment of ad hoc counsel, and then consider in greater detail the various investigative and pre-trial stages in which ad hoc counsel have been appointed. The authors further seek to identify the various issues which have arisen as a result of individual ad hoc counsel's conduct before the Court. Finally, they consider what impact the system of ad hoc counsel can have upon the fairness of subsequent trial proceedings, and what future developments in the system could promote the fairness of the overall proceedings before the Court.
Joint Criminal Enterprise: Cambodia's Reply to Tadić
Authors: Marsh Luke , Ramsden Michael
Published: January 2011

The doctrine of Joint Criminal Enterprise (JCE), which imposes individual criminal responsibility on an accused for their participation in a group's common criminal plan, rose to prominence in the ICTY Appeal Chamber decision, Prosecutor v. Tadić. Since Tadić, there has been a general reluctance by international ad hoc tribunals to review the legal foundation of JCE. However, on 20 May 2010, the ECCC Pre-Trial Chamber (PTC) considered the applicability of JCE to the atrocities which occurred in Cambodia during 1975-1979 - the period within the tribunal's temporal jurisdiction. The PTC has, unlike any other ad hoc tribunal to date, subjected the reasoning in Tadić to close scrutiny. This article will analyse the PTC's decision. In squarely contradicting Tadić on the expanded form of JCE, its findings are to be welcomed. The PTC's decision should be upheld on appeal in order to uphold the principle of legality; to safeguard the continued respect, credibility and future legacy of the ECCC trial process.
Effect of coupling agents on the dielectric properties of aluminum particles reinforced epoxy resin composites
Authors: Wenying Zhou  , Demei Yu
Published: January 2011

In this study, four kinds of coupling agents (i.e., silane KH550, silane KH560, titanate NXT-102, titanate NXT-201), were used to modify the surfaces of aluminum (Al) particles. The effects of these coupling agents on the microstructures and dielectric properties of the Al/epoxy composites were investigated by the scanning electron microscope (SEM) and dielectric analyzer. The SEM observations reveal that the use of coupling agents improved the interfacial bond strength between Al particles and epoxy resin, and decreased the voids and defects at the phase interfaces. The dielectric analysis indicate that the surface modification of Al particles had an appreciable effect on the dielectric permittivity of the composites at high filler concentration, that is, at 70 wt% Al particles (treated with silane KH560) content, the dielectric permittivity of the composites reached 34.1, as compared to 19.6 for the untreated filler reinforced one; however, the dielectric loss factors of the composites slightly decreased, and they remained at a very low level under various applied sweep frequencies despite the filler content.
Absence of Pharmacokinetic Interaction Between Roflumilast and Digoxin in Healthy Adults
Authors: Eckermann Gabriel , Lahu Gezim , Nassr Nassr , Bethke Thomas D.
Published: January 2011

Numerous interactions are known for digoxin, which is a drug with a narrow therapeutic index and a substrate of P‐glycoprotein (P‐gp). This study investigated potential effects of coadministration on pharmacokinetics and safety of both drugs when a single dose of digoxin was concomitantly administered with roflumilast under steady‐state conditions. Sixteen healthy male and female adults were randomly assigned in an open‐label, crossover study to either of 2 treatment sequences that consisted of 2 treatment periods separated by a washout phase. Treatments were oral daily doses of roflumilast for 14 days given concomitantly on days 1 and 14 with a single oral dose of digoxin or an oral dose of digoxin once on day 1. Plasma samples for pharmacokinetic evaluations of digoxin and roflumilast concentrations with and without concomitant treatment were taken. The rate of digoxin absorption was slightly (15%) but statistically insignificantly increased, whereas the extent of absorption was not altered by concomitant medication with roflumilast. Concomitant medication with digoxin did not significantly affect steady‐state pharmacokinetics of either roflumilast or its active metabolite roflumilast N‐oxide. Roflumilast is not an inhibitor of P‐gp. No safety or tolerability concerns were detected with coadministration of roflumilast and digoxin.
Standardized Visual Predictive Check Versus Visual Predictive Check for Model Evaluation
Authors: Wang Diane D. , Zhang Shuzhong
Published: January 2011

The visual predictive check (VPC) is a commonly used approach in model evaluation. However, it may not be feasible to conduct a VPC, or the results of a VPC could be misleading in certain situations. The objectives of the present study were to (1) examine the performance and applicability of the VPC and (2) propose the standardized visual predictive check (SVPC) as an alternative/complementary approach to the VPC. The difference between the SVPC and normalized prediction distribution error (npde) as visual tools for model evaluation is also discussed. The results of the simulation studies demonstrate that the VPC is not appropriate when stratification of covariate(s) in a model is difficult or arbitrary and may not be feasible when study design varies during a study/among participants. The SVPC addresses these issues by displaying the percentiles (Pi,j) of each participant's observations in the marginal distribution of the corresponding model‐simulated endpoints as a function of time (or any covariate of interest) based on that participant's own design template. Since the calculation of Pi,j factors out subject‐specific design features, the difference between observation and simulated values is only caused by misspecification of the structure model and/or inadequate estimation of random effect. Thus, the SVPC can be used in any situation.
Comparative Bioavailability of a Premixed, Ready‐to‐Use Formulation of Intravenous Amiodarone With Traditional Admixture in Healthy Subjects
Authors: Cushing Daniel J. , Adams Michael P. , Cooper Warren D. , Agha Bushra , Souney Paul F.
Published: January 2011

Intravenous amiodarone is an effective agent for the treatment of recurrent ventricular fibrillation and hemodynamically unstable ventricular tachycardia. PM101 Premixed Injection is a new formulation of intravenous amiodarone that uses a cyclodextrin to maintain amiodarone in the aqueous phase. Eighty‐eight subjects were enrolled in this randomized, single‐blind, crossover, bioequivalence clinical study and were treated with single doses (150 mg) of PM101 Premixed Injection and intravenous amiodarone separated by a washout period of at least 42 days. Venous blood samples were taken periodically during the first 72 hours after dosing to determine standard pharmacokinetic parameters. The geometric ratio of the area under the concentration‐time curve for time 0–72 hours (AUC0–72hr) for amiodarone was 0.96 (95% confidence interval [CI], 0.94–0.99). The geometric ratio of the maximum concentration (Cmax) for amiodarone was 0.87 (95% CI, 0.84–0.91). Because these ratios and their CI fell between the limits of 0.8 and 1.25, bioequivalence of these 2 formulations was established. No safety concerns unique to the PM101 Premixed Injection, ready‐to‐use formulation were identified.
Ready, Willing, and Able to Divorce: An Economic and Cultural History of Divorce in Twentieth-Century Sweden
Authors: Simonsson Per , Sandström Glenn
Published: January 2011

This study outlines a long history of divorce in Sweden, recognizing the importance of considering both economic and cultural factors in the analysis of marital dissolution. Following Ansley Coale, the authors examine how a framework of multiple theoretical constructs, in interaction, can be applied to the development toward mass divorce. Applying a long historical perspective, the authors argue that an analysis of gendered aspects of the interaction between culture and economics is crucial for the understanding of the rise of mass divorce. The empirical analysis finds support for a marked decrease in legal and cultural obstacles to divorce already during the first decades of the twentieth century. However, economic structures remained a severe obstacle that prohibited significant increases in divorce rate prior to World War II. It was only during the 1940s and 1960s, when cultural change was complemented by marked decreases in economic interdependence between spouses, that the divorce rate exhibited significant increases. The authors find that there are advantages to looking at the development of divorce as a history in which multiple empirical factors are examined in conjunction, recognizing that these factors played different roles during different time periods.
Biomechanical Evaluation of Pediatric Anterior Cruciate Ligament Reconstruction Techniques
Authors: Kennedy Abbey , Coughlin Dezba G. , Metzger Melodie F. , Tang Ronald , Pearle Andrew D. , Lotz Jeffrey C. , Feeley Brian T.
Published: January 2011

Background: Anterior cruciate ligament (ACL) reconstruction rates in skeletally immature patients have risen recently because of increased injury frequency combined with growing awareness of the importance of treating them in an acute setting. Concerns over potential growth disturbances caused by traditional tunnel placement have prompted the description of several partial and complete physeal-sparing techniques.

Hypothesis: Native knee kinematics will most closely be restored by the all-epiphyseal technique because it best re-creates the intra-articular ACL anatomy.

Study Design: Controlled laboratory study.

Methods: Six cadaveric knees were subjected to static anteroposterior, varus, and internal rotation forces at 0°,15°, 30°, 45°, 60°, and 90° of flexion. Displacement and rotation of the tibia with respect to the femur were measured in the intact knee, after ACL disruption, and again after ACL reconstruction using all-epiphyseal, transtibial over-the-top, and iliotibial band physeal-sparing techniques.

Results: Peak anteroposterior translation in the ACL intact and deficient states was 2.8 ± 1.4 mm and 7.2 ± 2.7 mm, respectively, at 30°. The all-epiphyseal reconstruction had a peak translation of 5.1 ± 2.3 mm at 30°, and the transtibial over-the-top reconstruction had a peak of 4.8 ± 1.8 mm at 30°, both significantly greater than the ACL intact state. The iliotibial band technique had a peak anteroposterior translation of 1.7 ± 1.1 mm at 45°, which was significantly less than the ACL-deficient state. Internal rotation was significantly increased in the all-epiphyseal reconstruction compared with the ACL intact state and significantly decreased at all flexion angles except 0° in the iliotibial band reconstruction. The only technique to affect varus rotation was the iliotibial band reconstruction, which significantly decreased varus rotation from the ACL-deficient state at flexion angles greater than 30°.

Conclusion: All physeal-sparing reconstruction techniques restored some stability to the knee. The iliotibial band reconstruction best restored anteroposterior stability and rotational control, although it appeared to overconstrain the knee to rotational forces at some flexion angles.

Clinical Relevance: This study provides orthopaedic surgeons with objective knee kinematic data to help guide them in making more informed decisions on the optimal technique for ACL reconstruction in skeletally immature patients.
Local Administration of Autologous Synovium-Derived Cells Improve the Structural Properties of Anterior Cruciate Ligament Autograft Reconstruction in Sheep
Authors: Kondo Eiji , Yasuda Kazunori , Katsura Taro , Hayashi Riku , Azuma Chinatsu , Tohyama Harukazu
Published: January 2011

Background: The structural properties of a tendon autograft deteriorate during the remodeling phase after anterior cruciate ligament (ACL) reconstruction.

Hypothesis: A local application of autologous synovium-derived cells cultured in medium supplemented with transforming growth factor β (TGFβ) may inhibit the deterioration of structural properties of the tendon graft after ACL reconstruction.

Study Design: Controlled laboratory study.

Methods: Fifty-two mature sheep were used. In each animal, the right knee underwent ACL reconstruction using the semitendinosus tendon autograft; then, the animals were divided into 5 groups of 10. No additional treatments were applied in group 1, whereas fibrin sealant was applied around the graft in group 2. In group 3, autologous synovium-derived cells cultured in standard medium were applied around the graft with fibrin sealant, whereas autologous synovium-derived cells cultured in TGFβ-supplemented medium were applied with fibrin sealant in group 4. In group 5, fibrin sealant containing 20 ng of TGFβ was applied around the graft. Each animal was sacrificed at 12 weeks after the surgery. In each group, 7 and 3 sheep were used for biomechanical and histologic evaluations, respectively. The remaining 2 sheep were used to confirm whether the applied cells infiltrated the graft at 1 week after surgery.

Results: Confocal microscope observations showed that the applied cells that were labeled before implantation infiltrated into the superficial portion of the graft at 1 week. Biomechanically, the maximum load and the stiffness of groups 4 and 5 were significantly greater than those of groups 1, 2, and 3. Histologically, necrotic lesions were observed in the core portion of the midsubstance in groups 1 and 2. In groups 3, 4, and 5, no necrotic lesions were found in the midsubstance.

Conclusion: A local application of autologous synovium-derived cells cultured in TGFβ-supplemented medium or a fibrin sealant containing TGFβ significantly inhibits the natural deterioration of the structural properties of the tendon graft after ACL reconstruction.

Clinical Relevance: Administration of autologous synovium-derived cells cultured in TGFβ-supplemented medium or TGFβ and fibrin glue alone can be a potential cell-based therapy to prevent graft deterioration after transplantation or accelerate mechanical restoration of the deteriorated graft.
Clinical and Magnetic Resonance Imaging–Based Outcomes to 5 Years After Matrix-Induced Autologous Chondrocyte Implantation to Address Articular Cartilage Defects in the Knee
Authors: Ebert Jay R. , Robertson William B. , Woodhouse Jennifer , Fallon Michael , Zheng M. H. , Ackland Timothy , Wood David J.
Published: January 2011

Background: The availability remains limited of midterm clinical and radiologic results into matrix-induced autologous chondrocyte implantation (MACI). Outcomes are required to validate the efficacy of MACI as a suitable surgical treatment option for articular cartilage defects in the knee.

Hypothesis: A significant improvement in clinical and magnetic resonance imaging–based (MRI-based) outcomes after MACI will exist throughout the postoperative timeline to 5 years after surgery. Furthermore, patient demographics, cartilage defect parameters, and injury/surgery history will be associated with patient and graft outcome, whereas a significant correlation will exist between clinical and MRI-based outcomes at 5 years after surgery.

Study Design: Case series; Level of evidence, 4.

Methods: A prospective evaluation was undertaken to assess clinical and MRI-based outcomes to 5 years in 41 patients (53 grafts) after MACI to the knee. After MACI surgery and a 12-week structured rehabilitation program, patients underwent clinical assessments (Knee injury and Osteoarthritis Outcome Score, SF-36, 6-minute walk test, knee range of motion) and MRI assessments at 3, 12, and 24 months, as well as 5 years after surgery. The MRI evaluation assessed 8 previously defined pertinent parameters of graft repair, as well as a combined MRI composite score.

Results: A significant improvement ( P < .05) was demonstrated for all Knee injury and Osteoarthritis Outcome Score and SF-36 subscales over the postoperative timeline, as well as the 6-minute walk test and active knee extension. A significant improvement ( P < .0001) was observed for the MRI composite score, as well as several individual graft scoring parameters. At 5 years after surgery, 67% of MACI grafts demonstrated complete infill, whereas 89% demonstrated good to excellent filling of the chondral defect. Patient demographics, cartilage defect parameters, and injury/surgery history demonstrated no significant pertinent correlations with clinical or MRI-based outcomes at 5 years, and no significant correlations existed between clinical and MRI-based outcome measures. At 5 years after surgery, 98% of patients were satisfied with the ability of MACI surgery to relieve knee pain; 86%, with improvement in their ability to perform normal daily tasks; and 73%, with their ability to participate in sport 5 years after MACI.

Conclusion: These results suggest that MACI provides a suitable midterm treatment option for articular cartilage defects in the knee. Long-term follow-up is essential to confirm whether the repair tissue has the durability required to maintain long-term patient quality of life.