bluuebunny/crossref_metadata_2025 huggingface dataset:
Two GABAergic Intraglomerular Circuits Differentially Regulate Tonic and Phasic Presynaptic Inhibition of Olfactory Nerve Terminals
Authors: Shao Z. , Puche A. C. , Kiyokage E. , Szabo G. , Shipley M. T.
Published: February 2009

Olfactory nerve axons terminate in olfactory bulb glomeruli forming excitatory synapses onto the dendrites of mitral/tufted (M/T) and juxtaglomerular cells, including external tufted (ET) and periglomerular (PG) cells. PG cells are heterogeneous in neurochemical expression and synaptic organization. We used a line of mice expressing green fluorescent protein under the control of the glutamic acid decarboxylase 65-kDa gene (GAD65+) promoter to characterize a neurochemically identified subpopulation of PG cells by whole cell recording and subsequent morphological reconstruction. GAD65+ GABAergic PG cells form two functionally distinct populations: 33% are driven by monosynaptic olfactory nerve (ON) input (ON-driven PG cells), the remaining 67% receive their strongest drive from an ON→ET→PG circuit with no or weak monosynaptic ON input (ET-driven PG cells). In response to ON stimulation, ON-driven PG cells exhibit paired-pulse depression (PPD), which is partially reversed by GABABreceptor antagonists. The ON→ET→PG circuit exhibits phasic GABAB-R-independent PPD. ON input to both circuits is under tonic GABAB-R-dependent inhibition. We hypothesize that this tonic GABABR-dependent presynaptic inhibition of olfactory nerve terminals is due to autonomous bursting of ET cells in the ON→ET→PG circuit, which drives tonic spontaneous GABA release from ET-driven PG cells. Both circuits likely produce tonic and phasic postsynaptic inhibition of other intraglomerular targets. Thus olfactory bulb glomeruli contain at least two functionally distinct GABAergic circuits that may play different roles in olfactory coding.
Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy
Authors: Kang Min H. , Reynolds C. Patrick
Published: February 2009

Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic pathway. It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins. Overexpression of anti-apoptotic Bcl-2 family members has been associated with chemotherapy resistance in various human cancers, and preclinical studies have shown that agents targeting anti-apoptotic Bcl-2 family members have preclinical activity as single agents and in combination with other antineoplastic agents. Clinical trials of several investigational drugs targeting the Bcl-2 family (oblimersen sodium, AT-101, ABT-263, GX15-070) are ongoing. Here, we review the role of the Bcl-2 family in apoptotic pathways and those agents that are known and/or designed to inhibit the anti-apoptotic Bcl-2 family of proteins.
Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer
Authors: Chen Eric , Jonker Derek , Gauthier Isabelle , MacLean Martha , Wells Julie , Powers Jean , Seymour Lesley
Published: February 2009

Purpose: Cediranib is a potent oral inhibitor of the tyrosine kinase activity associated with all subtypes of vascular endothelial growth factor receptor. Purposes of this study were to determine the recommended phase II dose of cediranib in combination with standard doses of modified FOLFOX-6 (mFOLFOX-6), and the tolerability, safety, pharmacokinetics, and antitumor activity of this combination in patients with untreated metastatic colorectal cancer.

Experimental Design: Cediranib was administered daily orally at a starting dose of 30 mg and escalated to 45 mg daily, and mFOLFOX-6 was repeated every 14 days. Pharmacokinetic studies were done for oxaliplatin, 5-fluorouracil, and cediranib. Response was assessed by Response Evaluation Criteria in Solid Tumors every four cycles.

Results: Sixteen patients received 150 cycles of treatment (median, 6; range, 1-20 cycles). Of 9 patients enrolled at the 30-mg dose level, 1 patient experienced grade 3 diarrhea during cycle 1. No dose-limiting toxicity was observed in 7 patients at the 45-mg dose level. Common grade 3 toxicities related to cediranib included hypertension, diarrhea, fatigue, and anorexia. Of 14 patients evaluable for response, there were 6 partial responses (42.9%; 95% confidence interval, 17.7-71.1%) and 6 stable disease. The median progression-free survival was 9.3 months. There were no pharmacokinetic interactions between cediranib and 5-fluorouracil or free plasma intact oxaliplatin.

Conclusions: Toxicities of this combination were manageable and consistent with previous studies. The recommended phase II dose is cediranib at 30 mg daily continuously in combination with standard doses of mFOLFOX-6. Cediranib and mFOLFOX-6 has promising antitumor activity and this combination warrants further investigation.
Mitotic Deregulation by Survivin in ErbB2-Overexpressing Breast Cancer Cells Contributes to Taxol Resistance
Authors: Lu Jing , Tan Ming , Huang Wen-Chien , Li Ping , Guo Hua , Tseng Ling-Ming , Su Xiao-hua , Yang Wen-Tao , Treekitkarnmongkol Warapen , Andreeff Michael , Symmans Fraser , Yu Dihua
Published: February 2009

Purpose: Taxol resistance remains a major obstacle to improve the benefit of breast cancer patients. Here, we studied whether overexpression of ErbB2 may lead to mitotic deregulation in breast cancer cells via up-regulation of survivin that confers Taxol resistance.

Experimental Design: ErbB2-overexpressing and ErbB2-low-expressing breast cancer cell lines were used to compare their mitotic exit rate, survivin expression level, and apoptosis level in response to Taxol. Survivin was then down-regulated by antisense oligonucleotides to evaluate its contribution to mitotic exit and Taxol resistance in ErbB2-overexpressing breast cancer cells. At last, specific PI3K/Akt and Src inhibitors were used to investigate the involvement of these two pathways in ErbB2-mediated survivin up-regulation and Taxol resistance.

Results: We found that ErbB2-overexpressing cells expressed higher levels of survivin in multiple breast cancer cell lines and patient samples. ErbB2-overexpressing cells exited M phase faster than ErbB2-low-expressing cells, which correlated with the increased resistance to Taxol-induced apoptosis. Down-regulation of survivin by antisense oligonucleotide delayed mitotic exit of ErbB2-overexpressing cells and also sensitized ErbB2-overexpressing cells to Taxol-induced apoptosis. Moreover, ErbB2 up-regulated survivin at translational level and PI3K/Akt and Src activation are involved. In addition, combination treatment of Taxol with PI3K/Akt and Src inhibitor led to increased apoptosis in ErbB2-overexpressing breast cancer cells than single treatment.

Conclusions: Survivin up-regulation by ErbB2 is a critical event in ErbB2-mediated faster mitotic exit and contributes to Taxol resistance.
Role of the Microenvironment for Radiosensitization by Patupilone
Authors: Bley Carla Rohrer , Jochum Wolfram , Orlowski Katrin , Furmanova Polina , Vuong Van , McSheehy Paul M.J. , Pruschy Martin
Published: February 2009

Purpose: The combined treatment modality of ionizing radiation (IR) and the clinically relevant microtubule-stabilizing compound patupilone (epothilone B, EPO906) is a promising approach for anticancer therapy. Here, we investigated the role of the tumor microenvironment for the supra-additive in vivo response in tumor xenografts derived from patupilone-sensitive and patupilone-resistant non-small cell lung cancer cells.

Experimental Design: The treatment response to a combined regimen of patupilone and IR was investigated in vitro and in tumor xenografts derived from wild-type A549 and A549.EpoB40 cells, which are resistant to patupilone due to a β-tubulin mutation.

Results: In both A549 and A549.EpoB40 cells, proliferative activity and clonogenicity were reduced in response to IR, whereas patupilone, as expected, inhibited proliferation of the mutant cell line with reduced potency. Combined treatment with patupilone and IR induced a cytotoxic effect in vitro in an additive way in A549 cells but not in the tubulin-mutated, patupilone-resistant A549.EpoB40 cells. A supra-additive tumor growth delay was induced by combined treatment in xenografts derived from A549 cells but not in xenografts derived from A549.EpoB40 cells. Histologic analysis revealed a significant decrease in tumor cell proliferation (Ki-67) and microvessel density and a treatment-dependent change of tumor hypoxia in A549 but not A549.EpoB40 xenografts.

Conclusions: Using a genetically defined patupilone-sensitive and patupilone-resistant tumor model, we here showed that the major cytotoxic effect of the combined treatment modality of IR and patupilone is directed against the tumor cell compartment. The induced antiangiogenic effect derives indirectly from the tumor cell.
A TaqMan Low-Density Array to Predict Outcome in Advanced Hodgkin's Lymphoma Using Paraffin-Embedded Samples
Authors: Sánchez-Espiridión Beatriz , Sánchez-Aguilera Abel , Montalbán Carlos , Martin Carmen , Martinez Rafael , González-Carrero Joaquín , Poderos Concepción , Bellas Carmen , Fresno Manuel F. , Morante Cesar , Mestre Maria J. , Mendez Miguel , Mazorra Francisco , Conde Eulogio , Castaño Angel , Sánchez-Godoy Pedro , Tomas José F. , Morente Manolo M. , Piris Miguel A. , García Juan F. ,   for the Spanish Hodgkin's Lymphoma Study Group
Published: February 2009

Purpose: Despite major advances in the treatment of classic Hodgkin's lymphoma (cHL), ∼30% of patients in advanced stages may eventually die as result of the disease, and current methods to predict prognosis are rather unreliable. Thus, the application of robust techniques for the identification of biomarkers associated with treatment response is essential if new predictive tools are to be developed.

Experimental Design: We used gene expression data from advanced cHL patients to identify transcriptional patterns from the tumoral cells and their nonneoplastic microenvironment, associated with lack of maintained treatment response. Gene-Set Enrichment Analysis was used to identify functional pathways associated with unfavorable outcome that were significantly enriched in either the Hodgkin's and Reed-Sternberg cells (regulation of the G2-M checkpoint, chaperones, histone modification, and signaling pathways) or the reactive cell microenvironment (mainly represented by specific T-cell populations and macrophage activation markers).

Results: To explore the pathways identified previously, we used a series of 52 formalin-fixed paraffin-embedded advanced cHL samples and designed a real-time PCR-based low-density array that included the most relevant genes. A large majority of the samples (82.7%) and all selected genes were analyzed successfully with this approach.

Conclusions: The results of this assay can be combined in a single risk score integrating these biological pathways associated with treatment response and eventually used in a larger series to develop a new molecular outcome predictor for advanced cHL.
Preclinical Studies in Support of Defibrotide for the Treatment of Multiple Myeloma and Other Neoplasias
Authors: Mitsiades Constantine S. , Rouleau Cecile , Echart Cinara , Menon Krishna , Teicher Beverly , Distaso Maria , Palumbo Antonio , Boccadoro Mario , Anderson Kenneth C. , Iacobelli Massimo , Richardson Paul G.
Published: February 2009

Purpose of the Study: Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation–related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further, given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma cells by bone marrow stromal cells.

Methods-Results: Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma cells with bone marrow stromal cells in vitro, defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myeloma–bone marrow stromal cell adhesion and its sequelae, including nuclear factor-κB activation in multiple myeloma and bone marrow stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines, and adhesion molecules.

Conclusion: Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in combination with conventional and novel therapies to potentially improve patient outcome in multiple myeloma and other malignancies.
Overexpression of Class III β-Tubulin Predicts Good Response to Taxane-Based Chemotherapy in Ovarian Clear Cell Adenocarcinoma
Authors: Aoki Daisuke , Oda Yoshinao , Hattori Satoshi , Taguchi Ken-ichi , Ohishi Yoshihiro , Basaki Yuji , Oie Shinji , Suzuki Nao , Kono Suminori , Tsuneyoshi Masazumi , Ono Mayumi , Yanagawa Takashi , Kuwano Michihiko
Published: February 2009

Purpose: Of the various microtubule-associated molecules, β-tubulin III has been reported to be closely associated with the therapeutic efficacy of taxane-based chemotherapy against ovarian cancer. Stathmin and microtubule-associated protein 4 (MAP4) have been reported to play an important role in microtubule stabilization. In this study, we investigated whether expression of these microtubule-associated factors affects the therapeutic efficacy of taxane-based chemotherapy in ovarian clear cell adenocarcinoma.

Experimental Design: Drug sensitivity of paclitaxel or cisplatin was assessed in ovarian cancer cell lines treated with small interfering RNA of tubulin isoforms, MAP4, and stathmin. We examined 94 surgically resected ovarian clear cell adenocarcinoma specimens from patients treated with taxane-containing regimens (n = 44) and with taxane-free regimens (n = 50), using immunohistochemistry to detect expression of β-tubulin III, stathmin, and MAP4.

Results: Knockdown of β-tubulin III and IV specifically conferred drug resistance to paclitaxel in one ovarian cancer cell line, but not to other molecules. Estimated overall survival revealed a significant synergistic effect between taxane and β-tubulin III in patients with ovarian clear cell adenocarcinoma. Of three microtubule-related molecules, among the taxane-based chemotherapy group, cases with higher β-tubulin III expression were associated with a significantly more favorable prognosis compared with those having lower β-tubulin III expression. By contrast, there was no statistical significance in the synergistic relationships between stathmin and taxane or between MAP4 and taxane.

Conclusions: Taxane-based chemotherapy was effective for patients with ovarian clear cell adenocarcinomas who were positive for β-tubulin III but not for those who were negative for these proteins.
Pharmacologic Unmasking of Epigenetically Silenced Genes in Breast Cancer
Authors: Ostrow Kimberly Laskie , Park Hannah Lui , Hoque Mohammad Obaidul , Kim Myoung Sook , Liu Junwei , Argani Pedram , Westra William , Criekinge Wim Van , Sidransky David
Published: February 2009

Purpose: Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of various cancers including breast cancer. Many epigenetically inactivated genes involved in breast cancer development remain to be identified. Therefore, in this study we used a pharmacologic unmasking approach in breast cancer cell lines with 5-aza-2′-deoxycytidine (5-aza-dC) followed by microarray expression analysis to identify epigenetically inactivated genes in breast cancer.

Experimental Design: Breast cancer cell lines were treated with 5-aza-dC followed by microarray analysis to identify epigenetically inactivated genes in breast cancer. We then used bisulfite DNA sequencing, conventional methylation-specific PCR, and quantitative fluorogenic real-time methylation-specific PCR to confirm cancer-specific methylation in novel genes.

Results: Forty-nine genes were up-regulated in breast cancer cells lines after 5-aza-dC treatment, as determined by microarray analysis. Five genes (MAL, FKBP4, VGF, OGDHL, and KIF1A) showed cancer-specific methylation in breast tissues. Methylation of at least two was found at high frequency only in breast cancers (40 of 40) as compared with normal breast tissue (0 of 10; P < 0.0001, Fisher's exact test).

Conclusions: This study identified new cancer-specific methylated genes to help elucidate the biology of breast cancer and as candidate diagnostic markers for the disease.
Curcumin Inhibits Prosurvival Pathways in Chronic Lymphocytic Leukemia B Cells and May Overcome Their Stromal Protection in Combination with EGCG
Authors: Ghosh Asish K. , Kay Neil E. , Secreto Charla R. , Shanafelt Tait D.
Published: February 2009

Purpose: Chronic lymphocytic leukemia (CLL) is incurable with current chemotherapy treatments. Curcumin (diferuloylmethane), an active ingredient in the spice turmeric, inhibits tumor metastasis, invasion, and angiogenesis in tumor cell lines. We evaluated the effects of curcumin on the viability of primary CLL B cells and its ability to overcome stromal mediated protection.

Experimental Design: The in vitro effect of curcumin on primary CLL B cells was evaluated using fluorescence activated cell sorter analysis and Western blotting. For some experiments, CLL B cells were cocultured with human stromal cells to evaluate the effects of curcumin on leukemia cells cultured in their microenvironment. Finally, the effect of curcumin in combination with the green tea extract epigallocatechin-3 gallate (EGCG) was evaluated.

Results: Curcumin induced apoptosis in CLL B cells in a dose-dependent (5-20 μmol/L) manner and inhibited constitutively active prosurvival pathways, including signal transducers and activators of transcription 3 (STAT3), AKT, and nuclear factor κB. Moreover, curcumin suppressed expression of the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), and up-regulated the pro-apoptotic protein BIM. Coculture of CLL B cells with stromal cells resulted in elevated levels of STAT3, increased expression of Mcl-1 and XIAP, and decreased sensitivity to curcumin. When curcumin was administered simultaneously with EGCG, antagonism was observed for most patient samples. In contrast, sequential administration of these agents led to substantial increases in CLL B-cell death and could overcome stromal protection.

Conclusions: Curcumin treatment was able to overcome stromal protection of CLL B cells on in vitro testing and to synergize with EGCG when administered in a sequential fashion. Additional evaluation of curcumin as a potential therapeutic agent for treatment of CLL seems warranted.
Soy-Derived Isoflavones Inhibit the Growth of Canine Lymphoid Cell Lines
Authors: Jamadar-Shroff Vahbiz , Papich Mark G. , Suter Steven E.
Published: February 2009

Purpose: This study aimed to evaluate the in vitro effects of genistein, both pure genistein and a commercially available form of genistein called Genistein Combined Polysacharride (GCP), against two canine B-cell lymphoid cell lines and determine the oral bioavailability of GCP when fed to normal dogs.

Experimental Design: The in vitro effect of genistein and GCP was evaluated using cell proliferation and apoptotic assays. The IC50 of both compounds was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay and propidium idodide staining. Apoptosis was evaluated using Annexin V staining, caspase 3 and 9 staining, and DNA laddering. Cell cycle analysis and Bcl-2/Bax ratios were also examined. An initial dose escalating pharmacokinetic study was used to determine if therapeutic serum levels of genistein could be reached with oral dosing of GCP in normal dogs.

Results: The 72-hour in vitro IC50 of genistein and GCP against the GL-1 and 17-71 cells were both 10 μg/mL and 20 μg/mL, respectively. GCP led to cell death in both cell lines via apoptosis and treated cells exhibited increased Bax:Bcl-2 ratios. The serum concentrations of genistein in normal dogs given increasing oral doses of GCP did not reach the 72-hour in vitro IC50 in a dose escalation study.

Conclusions: The results of these studies support the notion that canine high-grade B-cell lymphoma may represent a relevant large animal model of human non-Hodgkin's lymphoma to investigate the utility of GCP in chemopreventive and/or treatment strategies that may serve as a prelude to human clinical lymphoma trials.
A Genetic Expression Profile Associated with Oral Cancer Identifies a Group of Patients at High Risk of Poor Survival
Authors: Méndez Eduardo , Houck John R. , Doody David R. , Fan Wenhong , Lohavanichbutr Pawadee , Rue Tessa C. , Yueh Bevan , Futran Neal D. , Upton Melissa P. , Farwell D. Gregory , Heagerty Patrick J. , Zhao Lue Ping , Schwartz Stephen M. , Chen Chu
Published: February 2009

Purpose: To determine if gene expression signature of invasive oral squamous cell carcinoma (OSCC) can subclassify OSCC based on survival.

Experimental Design: We analyzed the expression of 131 genes in 119 OSCC, 35 normal, and 17 dysplastic mucosa to identify cluster-defined subgroups. Multivariate Cox regression was used to estimate the association between gene expression and survival. By stepwise Cox regression, the top predictive models of OSCC-specific survival were determined and compared by receiver operating characteristic analysis.

Results: The 3-year overall mean ± SE survival for a cluster of 45 OSCC patients was 38.7 ± 0.09% compared with 69.1 ± 0.08% for the remaining patients. Multivariate analysis adjusted for age, sex, and stage showed that the 45 OSCC patient cluster had worse overall and OSCC-specific survival (hazard ratio, 3.31; 95% confidence interval, 1.66-6.58 and hazard ratio, 5.43; 95% confidence interval, 2.32-12.73, respectively). Stepwise Cox regression on the 131 probe sets revealed that a model with a term for LAMC2 (laminin γ2) gene expression best identified patients with worst OSCC-specific survival. We fit a Cox model with a term for a principal component analysis-derived risk score marker and two other models that combined stage with either LAMC2 or PCA. The area under the curve for models combining stage with either LAMC2 or PCA was 0.80 or 0.82, respectively, compared with 0.70 for stage alone (P = 0.013 and 0.008, respectively).

Conclusions: Gene expression and stage combined predict survival of OSCC patients better than stage alone.
Combining the Endoplasmic Reticulum Stress–Inducing Agents Bortezomib and Fenretinide as a Novel Therapeutic Strategy for Metastatic Melanoma
Authors: Hill David S. , Martin Shaun , Armstrong Jane L. , Flockhart Ross , Tonison Joge J. , Simpson Dominic G. , Birch-Machin Mark A. , Redfern Christopher P.F. , Lovat Penny E.
Published: February 2009

Purpose: Single-agent chemotherapy is largely the treatment of choice for systemic therapy of metastatic melanoma, but survival rates are low, and novel adjuvant and systemic therapies are urgently required. Endoplasmic reticulum (ER) stress is a potential therapeutic target, and two relatively new drugs, fenretinide and bortezomib (Velcade), each acting via different cellular mechanisms, induce ER stress leading to apoptosis in melanoma cells. The aim of this study was to test the hypothesis that apoptosis of melanoma cells may be increased by combining clinically achievable concentrations of fenretinide and bortezomib.

Experimental Design: Three human melanoma cell lines were used to assess changes in viability and the induction of apoptosis in response to fenretinide, bortezomib, or both drugs together. A s.c. xenograft model was used to test responses in vivo.

Results: Fenretinide and bortezomib synergistically decreased viability and increased apoptosis in all three melanoma lines at clinically achievable concentrations. This was also reflected by increased expression of GADD153, a marker of ER stress-induced apoptosis. In vivo, fenretinide in combination with bortezomib gave a marked reduction in xenograft tumor volume and an increase in apoptosis compared with fenretinide or bortezomib alone. The cell cycle stage of tumor cells in vivo were similar to that predicted from the effects of each drug or the combination in vitro.

Conclusions: These results suggest that fenretinide and bortezomib, both of which are available in clinical formulation, warrant clinical evaluation as a combination therapy for metastatic melanoma.
Interaction of Activation–Repolarization Coupling and Restitution Properties in Humans
Authors: Hanson Ben , Sutton Peter , Elameri Nasser , Gray Marcus , Critchley Hugo , Gill Jaswinder S. , Taggart Peter
Published: February 2009

Background—

Dynamic modulation of repolarization is important in arrhythmogenesis. An inverse relation exists in myocardium between activation time (AT) and action potential duration (APD). We hypothesized that resulting gradients of APD and diastolic interval (DI) interact with restitution properties and modulate the timing of repolarization.

Methods and Results—

Activation-recovery intervals (ARI) were acquired from reconstructed noncontact unipolar electrograms from the left ventricular endocardium in 9 patients (7 male) with normal ventricles. At a basic paced cycle length (median, 450 ms), ARIs shortened along the path of activation, with a mandatory reciprocal increase of DIs. In the median patient, this range of DIs started at 230 ms at the site of earliest activation and increased to 279 ms at the site of latest activation at a basic cycle length of 450 ms. Four consecutive standard S1 to S2 restitution curves were performed. At sites with a longer ARI (and therefore shorter DI) close to the site of stimulation, premature stimulation produced more shortening of ARIs; therefore, the time course of restitution was steeper than at more distal sites. At normal heart rate, the decrease in ARIs along the conduction pathway compensated for later activation. Thus, dispersion in repolarization time (RT) is smaller than dispersion in ARI in a heart with a steep negative AT–ARI relationship. This protective effect is lost in hearts without such a relationship. In the patients with a steep AT–ARI relationship at basic cycle length, this relation is lost after premature stimulation and is a function of prematurity. Thus, dispersion in RT is larger after shortly coupled extra stimuli in patients with a steep AT–ARI relationship.

Conclusions—

A complex interplay exists between activation–repolarization coupling and restitution properties, largely driven by ARI and DI gradients. This plays a significant role in the dynamics of repolarization in humans.
Preshock Cardiopulmonary Resuscitation Worsens Outcome From Circulatory Phase Ventricular Fibrillation With Acute Coronary Artery Obstruction in Swine
Authors: Indik Julia H. , Hilwig Ronald W. , Zuercher Mathias , Kern Karl B. , Berg Marc D. , Berg Robert A.
Published: February 2009

Background—

Some clinical studies have suggested that chest compressions before defibrillation improve survival in cardiac arrest because of prolonged ventricular fibrillation (VF; ie, within the circulatory phase). Animal data have also supported this conclusion, and we have previously demonstrated that preshock chest compressions increase the VF median frequency and improve the likelihood of a return of spontaneous circulation in normal swine. We hypothesized that chest compressions before defibrillation in a swine model of acute myocardial ischemia would also increase VF median frequency and improve resuscitation outcome.

Methods and Results—

Twenty-six swine were subjected to balloon occlusion of the left anterior descending coronary artery for 2 hours. The balloon was removed and VF was induced and untreated for 8 minutes. Swine were then treated with up to 3 stacked defibrillation shocks (n=13, shock-first group) or 3 minutes of chest compressions before shock (n=13, preshock cardiopulmonary resuscitation group). In the preshock cardiopulmonary resuscitation group, median frequency was increased from 7.0�0.8 to 13.9�1.6 Hz after chest compressions (
P
=0.002). Despite the improved median frequency in the preshock cardiopulmonary resuscitation group, 24-hour survival with favorable neurological status was significantly worse in the preshock cardiopulmonary resuscitation group (1/13) compared with the shock-first group (8/13,
P
=0.01).

Conclusions—

In a swine model of prolonged VF in acute myocardial ischemia, 24-hour survival with favorable neurological status was more likely when defibrillation was performed first without preceding chest compressions. Myocardial substrate is an important factor in determining the optimal resuscitation strategy.
Time-Warped Comparison of Gene Expression in Adaptive and Maladaptive Cardiac Hypertrophy
Authors: Sheehy Sean P. , Huang Sui , Parker Kevin Kit
Published: February 2009

Background—

Cardiac hypertrophy is classically regarded as a compensatory response, yet the active tissue remodeling processes triggered by various types of mechanical stress can enhance or diminish the function of the heart. Despite the disparity in outcomes, there are similarities in the hypertrophic responses. We hypothesized that a generic genetic response that is not dependent on the particular nature of the hypertrophic stimulus exists. To test our hypothesis, we compared the temporal evolution of transcriptomes measured in hearts subjected to either adaptive (exercise-induced) or maladaptive (aortic banding–induced) hypertrophy.

Methods and Results—

Generic hypertrophy-associated genes were identified and distinguished from stimulus-dependent transcripts by coupling a metric of cardiac growth with a dynamic time-warping algorithm to align transcriptome changes with respect to the hypertrophy response. The major differences in expression between the adaptive and maladaptive hypertrophy models were centered around the genes involved in metabolism, fibrosis, and immune response. Conversely, transcripts with common expression patterns in both hypertrophy models were associated with signal transduction, cytoskeletal development, and muscle contraction. Thus, despite the apparent differences in the expression response of the heart to either athletic conditioning or pressure overload, there is a set of genes that displays similar expression profiles.

Conclusions—

This finding lends support to the notion of a generalized cardiac growth mechanism that is activated in response to mechanical perturbation. The common and unique genetic signatures of adaptive and maladaptive hypertrophy may be useful in the diagnosis and treatment of pathological myocardial remodeling.
Q 4:24 revisited
Authors: Witztum Joseph
Published: February 2009

Q 4:24 has presented a challenge to classical exegetes and modern scholars alike. Examining Quranic evidence and the exegetical tradition, this article offers a textual analysis of this verse and suggests a new reading. I argue that the first part of Q 4:24 is an independent sentence; that an erroneous reading of it as a continuation of the previous verse led to the replacement of the original meaning of muhsināt (chaste women) with married women; and that there is a strong case for understanding the second part of the verse as addressing mut'a.
Sources of Moral Obligation to non-Muslims in the "Jurisprudence of Muslim Minorities" (Fiqh al-aqalliyyāt) Discourse
Authors: March Andrew
Published: February 2009

This article surveys four approaches towards moral obligation to non-Muslims found in Islamic legal thought. I refer to the first three approaches as the "revelatory-deontological," the "contractualist-constructivist" and the "consequentialist-utilitarian." The main argument is that present in many contemporary works on the "jurisprudence of Muslim minorities" (fiqh al-aqalliyyāt) is an attempt to provide an Islamic foundation for a relatively thick and rich relationship of moral obligation and solidarity with non-Muslims. This attempt takes the form of a fourth "comprehensive-qualitative" approach to political ethics that appeals not to juridical reasoning of the type "is x permissible and in which conditions?" but rather to Islamic ideals of what it means to live a good life, of what believing, normatively-committed Muslims want to pursue in this world. This meta-ethical approach builds on and goes beyond the first three. This fourth "comprehensive-qualitative" approach to moral obligation to non-Muslims is novel, emergent and not found in the writings of outright reformers but in those of conservative, "neo-classical," sharī'a-minded—even Muslim Brotherhood-affiliated—Muslim scholars. What adds to the force of this argument is that the other meta-ethical discourses, particularly of contract and utility (maslaha), already get these scholars quite far towards a doctrine of "loyal resident alienage" in non-Muslim societies. That even orthodox Muslim scholars go further shows that they have some interest in giving a theological or principled foundation to a much thicker and richer form of moral obligation to non-Muslims, a relationship which involves recognizing non-Muslims qua non-Muslims and contributing to their well-being.
Feminei Furores. Prudentius' Hamartigenia and the Epigramma Paulini
Authors: Chiappiniello Roberto
Published: February 2009

The Epigramma Paulini is a late antique Gallo-Roman poem of uncertain authorship which contains a dialogue structured on the model of the first Vergilian Eclogue. It is an unusual pastoral poem as it blends pastoral with satire. Recent scholarship has focused on the way the author of the Epigramma Paulini adapts the Vergilian model to suit his Christian message. The aim of this paper is to explore more fully the satirical section of the poem and, in particular, the lines focusing on Roman vices which contain a striking attenuation of the topos of misogyny. I seek to show through verbal and thematic similarities that the model for this part of the poem is the Hamartigenia of Prudentius.
Cloning and expression of PKG, a candidate foraging regulating gene in Vespula vulgaris
Authors: Tobback Julie , Heylen Kevin , Gobin Bruno , Wenseleers Tom , Billen Johan , Arckens Lut , Huybrechts Roger
Published: February 2009

In honey bees, enhancement of cGMP-dependent protein kinase (PKG) expression accompanies a behavioural transition from in-hive working nursing bees towards outdoors foraging worker bees. Accordingly this gene was named amfor or Apis mellifera foraging gene. In the red harvester ant Pogonomyrmex barbatus a gene homologue affected food seeking behaviour as well, but in this species PKG expression decreased from the onset of foraging behaviour. Since the wasp Vespula vulgaris is phylogenetically positioned between ants and bees, in this paper we tried to elucidate whether the involvement of PKG in foraging behaviour can be extended to this species and if so, whether its expression is enhanced or decreased by the transition from nursing to foraging. To enable this candidate gene approach, we first had to clone the PKG homologue from the common wasp. QPCR indicated a relevantly higher expression of Vvfor in nursing versus foraging wasps although interpretation of the results was hampered by a remarkable degree of variation as could be predicted from wasps captured in the wild as a source for mRNA extraction and quantification.
Riverbank assessment and management for the Eurasian otter in the north of Luxembourg
Authors: Schmidt Gérard , L'Hoste Lionel , Dohet Alain , Boscher Aurore , Cauchie Henry-Michel , Hoffmann Lucien
Published: February 2009

The presence of habitats such as burrows and dense willows along the rivers is very important for the survival of the European otter in terms of structures allowing quiet living conditions and possibilities for reproduction. To prevent the extinction of the otter in Luxembourg and nearby areas, an assessment of otter habitats and populations was made in 1994. This first evaluation has demonstrated that only rivers in the north of Luxembourg were suitable for otter populations in terms of quality of habitats and that only a few individuals were still present in this part of the country. In 2007, a new habitat assessment was carried out to define priorities for the management of habitats and to build or rebuild corridors to support otter migration and allow re-establishment of stable otter populations in the Benelux Countries. Two similar methods were used to assess quality of habitats in 1994 and 2007. The results of the habitat assessment are different for the Mid Sûre River and similar for the River Wiltz, the River Wark, the River Our and the Upper Sûre River. This variation is probably due to assessment complexity and observer subjectivity, but also to the difficulty to have a practical methodology for management priorities. From this point of view it would be useful to have a standard methodology at the European level to assess otter habitats.
Minority Rights Issues in Nigeria: A Theoretical Analysis of Historical and Contemporary Conflicts in the Oil-Rich Niger Delta Region
Authors: Ako Rhuks , Okonmah Patrick
Published: February 2009

Nigeria's delta region was famous for its role in the trade and supply of palm-oil to the then industrialising world. Thereafter, its high quality crude-oil made it a significant player in the global oil market. However, the region has become (in)famous for the spate of violent conflicts that threaten both local and international economic stability and security. This paper highlights the correlations between these two eras, the parties and fundamental causes of the violent conflicts that beset the area. It argues that the underlying factor for restiveness in both periods is the exclusion of the local communities from participating in the exploitation and benefits of the resources. The paper theorises the causes of conflicts during the two periods based on social justice concepts of distribution and recognition. It suggests that the actualisation of normative elements of distribution and recognition that quelled the first of these conflicts has a fundamental role to play in resolving the multifarious conflicts that currently pervade the Niger Delta region. Consequently, it suggests that initiatives that recognise public participation in the crude-oil industry be extended to resolve the present conflicts.
The New Developments Regarding the Saami Peoples of the North
Authors: Fitzmaurice Malgosia
Published: February 2009

This article will explore the new developments regarding the Saami peoples of Northern Europe. In particular it will be focused on new legislation promulgated in Norway and the Draft Saami Convention and their right to self-determination.
The Role of Courts in Adversarial Litigation in Russia
Authors: Reshetnikova Irina
Published: February 2009

Modern Russian arbitrazh court and civil court procedure (since 2002) has many adversarial characteristics, which are similar to those of British and American courts but which have their roots the Imperial Russian legal reform of 1864. This article offers the reader an analysis of the main features of Russian procedural legislation.
Constitutional Justice in Russia
Authors: Henderson Jane , Lomovtseva Marina
Published: February 2009

The 1993 Russian Constitution and 1994 Federal Constitutional Law “On the Constitutional Court of the Russian Federation” define the jurisdiction and activity of the Federal Constitutional Court of the Russian Federation. However, these pieces of legislation do not comprehensively address all the issues, and there has been some broadening of the Court's power through interpretation and the effect of some other legislation. This article examines the Court's jurisdiction and some of the issues that arise in the exercise thereof, as well as the relative role of the constitutional or charter courts of the subjects of the Federation, and the relationship between the Constitutional Court and the other courts in the Russian federal system. Issues of the methods of constitutional interpretation are addressed. The importance of the Constitutional Court as the federal agency of constitutional court supervision (review) in ensuring the effective application of the Russian Constitution is highlighted in the context of this growth of a comparatively new branch of law in the Russian legal system.
Transnational Investments in Informational Capital
Authors: Munk Martin D.
Published: February 2009

In this article, I analyse the acquisition of informational capital, i.e. academic capital, measured as student mobility and understood as transnational investments in prestigious foreign educational institutions. In the 1990s, educational `zones of prestige' were the United States, the United Kingdom and, to some extent, Germany and France. Official statistics from Sweden, Denmark and France regarding the outflow of students reflect increasing student mobility. In particular, the study reveals that students from the upper and upper-middle social classes (measured by parental occupation) are more likely than students from other social classes to pursue transnational investments, even though students from the middle and working classes have now entered the arena. This has also been found in a recent analysis of Danish academic emigrants. All in all, studies confirm the hypothesis that students from the upper classes are more likely than others to invest in specific informational capital in the field of education, in national environments and in international settings.
Men, Masculinities and Heart Disease
Authors: Emslie Carol , Hunt Kate
Published: February 2009

The aim of this study was to synthesize qualitative data on men's experiences of coronary heart disease (CHD). The authors searched for qualitative papers published before January 2007 in MEDLINE, EMBASE, British Nursing Index, CINAHL, PsychINFO and Web of Knowledge and used thematic analysis to synthesize findings. They found 136 studies that collected data on men's experiences of CHD. Only 27 studies took a gendered approach and only two aimed to investigate men's gendered experiences of CHD. Many men drew on discourses associated with hegemonic masculinity (e.g. demonstrating stoicism through delaying seeking professional help) when talking about the implications of the disease for their identity, relationships and paid work. However, some accounts challenged this dominant discourse. The authors argue that a more nuanced understanding of hegemonic masculinity should take account of the production of gendered narratives in the interview context, given that men `do' gender when they give the impression of `not doing' health.
Gender, Sexuality and Embodiment
Authors: Edwards Jane , van Roekel Helen
Published: February 2009

This article identifies the way same-sex attracted women negotiate healthcare in a rural Australian setting. In-depth interviews were conducted with 10 women. Respondents choose general practitioners (GPs) carefully, `interviewing' them to see if they hold acceptable attitudes to same-sex attraction. However, sexuality is not the only evaluative criteria women use. Some women invoke gender-based discourse, evaluating GPs by how well they treat women's bodies. In other instances, women utilize a framework based on sexuality; good healthcare is associated with how the practitioner dealt with same-sex attraction. Sometimes women evaluated care by reference to a model of the body that did not implicate gender or sexuality and GPs are evaluated on the basis of clinical knowledge. This shows that women do not define themselves in a unitary way in relation to gender or sexuality. They selectively and strategically employ discourses of gender, sexuality and embodiment to structure and evaluate healthcare.
History, buranjis and nation
Authors: Saikia Arupjyoti
Published: February 2009

How was history read and written in early twentieth-century Assam? Was it strikingly different from contemporary Indian practices? This article investigates these issues while carrying out a biographical reconstruction of Assamese historian Suryya Kumar Bhuyan. Bhuyan’s ambivalence in choosing a paradigm for historical pursuit is clear. For instance, while he endeavoured to escape from the contemporary historical practices based on rationalist-positivist model, he also continued to use two parallel forms of understanding of past: history and literature.

While he meticulously invested his energy in the building of a modern archival repository of sources, he was equally interested in addressing the needs of two competing consumers of the past: his peers and the Assamese readers. This article talks about how Bhuyan, trained both in literature and historical studies, published extensively in both English and Assamese, wrote professional and popular history, built up a resourceful archive, and stood defiantly amidst the competing Western and Assamese practices of recounting the past.
On national identity, nationalism and Soccer 2010
Authors: Sewpaul Vishanthie
Published: February 2009

English

There is a wide spectrum of views on the potential socio-economic and socio-political consequences of South Africa hosting the Soccer 2010 World Cup. This article discusses whether this major sports event holds potential to contribute to a strengthened national identity and consciousness and/or to a narrow nationalism, and looks at possible implications for society and social work.

French

Il existe un large éventail de points de vue sur les conséquences socioéconomiques et sociopolitiques de la tenue du Mondial de football 2010 en Afrique du Sud. Cet article examine si cet événement sportif de grande envergure peut contribuer à renforcer la conscience et l’identité nationale ou au contraire donner lieu à un nationalisme étroit, et il envisage les conséquences possibles sur la société et le travail social.

Spanish

Son muchos los puntos de vista acerca de posibles consecuencias socioeconómicas y sociopolíticas de que la Copa Mundial del 2010 tenga lugar en Sudáfrica. Se explora si este importante evento deportivo tiene el potencial de contribuir a fortalecer la identidad y conciencia nacional, y/o un nacionalismo estrecho. Se examinan las posibles implicaciones para la sociedad y el trabajo social.