bluuebunny/crossref_metadata_2025 huggingface dataset:
Fractal dynamics of human gait: a reassessment of the 1996 data of Hausdorff et al.
Authors: Delignières Didier , Torre Kjerstin
Published: February 2009

We propose in this paper a reassessment of the original data of Hausdorff et al. (Hausdorff JM, Purdon PL, Peng C-K, Ladin Z, Wei JY, Goldberger AR. J Appl Physiol 80: 1448–1457, 1996). We confirm, using autoregressive fractionally integrated moving average modeling, the presence of genuine fractal correlations in stride interval series in self-paced conditions. In contrast with the conclusions of the authors, we show that correlations did not disappear in metronomic conditions. The series of stride intervals presented antipersistent correlations, and 1/ f fluctuations were evidenced in the asynchronies to the metronome. We show that the super central pattern generator model (West B, Scafetta N. Phys Rev E Stat Nonlin Soft Matter Phys 67: 051917, 2003) allows accounting for the experimentally observed correlations in both self-paced and metronomic conditions, by the simple setting of the coupling strength parameter. We conclude that 1/ f fluctuations in gait are not overridden by supraspinal influences when walking is paced by a metronome. The source of 1/ f noise is still at work in this condition, but expressed differently under the influence of a continuous coupling process.
A new model of chronic intermittent hypoxia in humans: effect on ventilation, sleep, and blood pressure
Authors: Tamisier R. , Gilmartin G. S. , Launois S. H. , Pépin J. L. , Nespoulet H. , Thomas R. , Lévy P. , Weiss J. W.
Published: February 2009

Obstructive sleep apnea is characterized by repetitive nocturnal upper airway obstructions that are associated with sleep disruption and cyclic intermittent hypoxia (CIH) The cyclic oscillations in O2 saturation are thought to contribute to cardiovascular and other morbidity, but animal and patient studies of the pathogenic link between CIH and these diseases have been complicated by species differences and by the effects of confounding factors such as obesity, hypertension, and impaired glucose metabolism. To minimize these limitations, we set up a model of nocturnal CIH in healthy humans. We delivered O2 for 15 s every 2 min during sleep while subjects breathed 13% O2 in a hypoxic tent to create 30 cycles/h of cyclic desaturation-reoxygenation [saturation of peripheral O2 (SpO2) range: 95–85%]. We exposed subjects overnight for 8–9 h/day for 2 wk (10 subjects) and 4 wk (8 subjects). CIH exposure induced respiratory disturbances (central apnea hypopnea index: 3.0 ± 1.9 to 31.1 ± 9.6 events/h of sleep at 2 wk). Exposure to CIH for 14 days induced an increase in slopes of hypoxic and hypercapnic ventilatory responses (1.5 ± 0.6 to 3.1 ± 1.2 l·min−1·% drop in SpO2 and 2.2 ± 1.0 to 3.3 ± 0.9 l·min−1·mmHg CO2−1, respectively), consistent with hypoxic acclimatization. Waking normoxic arterial pressure increased significantly at 2 wk at systolic (114 ± 2 to 122 ± 2 mmHg) and for diastolic at 4 wk (71 ± 1.3 to 74 ± 1.7 mmHg). We propose this model as a new technique to study the cardiovascular and metabolic consequences of CIH in human volunteers.
Quantification of Optical Images of Cortical Responses for Inferring Functional Maps
Authors: Purushothaman Gopathy , Khaytin Ilya , Casagrande Vivien A.
Published: February 2009

Optical imaging of cortical signals enables the mapping of functional organization across large patches of cortex with good spatial resolution. But techniques for the quantitative analysis and interpretation of these images are limited. Frequently the functional architecture of the cortex is inferred from the visible topography of cortical reflectance images averaged or differenced across stimulus conditions and scaled or color-coded for presentation. Such qualitative assessments have sometimes led to divergent conclusions particularly about the organization of spatial and temporal frequency preferences in the primary visual cortex. We applied quantitative methods derived from signal detection theory to objectively interpret optical images. The differential response to any two arbitrary stimuli was represented at each pixel as the probability of discriminating between the two stimuli given the reflectance values at that pixel. These probability maps reduced false alarms and provided better signal-to-noise ratio in fewer trials than difference maps. We applied these methods to optical images of primate primary visual area (V1) obtained in response to sinusoidal gratings of different orientations and spatiotemporal frequencies. Clustering by orientation preference was stronger than that for spatial frequency, whereas clustering by temporal frequency preference was the weakest, largely in agreement with a previous electrophysiological study that quantified the degree of clustering of neurons for various response properties using uniform, quantitative criterion. We suggest that probability maps can extend the applicability of optical imaging to investigations of finer aspects of cortical functional organization through better signal-to-noise ratio and uniform, quantitative criteria for interpretation.
Presynaptic Muscarinic Receptors Enhance Glutamate Release at the Mitral/Tufted to Granule Cell Dendrodendritic Synapse in the Rat Main Olfactory Bulb
Authors: Ghatpande Ambarish S. , Gelperin Alan
Published: February 2009

The mammalian olfactory bulb receives multiple modulatory inputs, including a cholinergic input from the basal forebrain. Understanding the functional roles played by the cholinergic input requires an understanding of the cellular mechanisms it modulates. In an in vitro olfactory bulb slice preparation we demonstrate cholinergic muscarinic modulation of glutamate release onto granule cells that results in γ-aminobutyric acid (GABA) release onto mitral/tufted cells. We demonstrate that the broad-spectrum cholinergic agonist carbachol triggers glutamate release from mitral/tufted cells that activates both AMPA and NMDA receptors on granule cells. Activation of the granule cell glutamate receptors leads to calcium influx through voltage-gated calcium channels, resulting in spike-independent, asynchronous GABA release at reciprocal dendrodendritic synapses that granule cells form with mitral/tufted cells. This cholinergic modulation of glutamate release persists through much of postnatal bulbar development, suggesting a functional role for cholinergic inputs from the basal forebrain in bulbar processing of olfactory inputs and possibly in postnatal development of the olfactory bulb.
The Synergistic Organization of Muscle Recruitment Constrains Visuomotor Adaptation
Authors: de Rugy Aymar , Hinder Mark R. , Woolley Daniel G. , Carson Richard G.
Published: February 2009

Reaching to visual targets engages the nervous system in a series of transformations between sensory information and motor commands. That which remains to be determined is the extent to which the processes that mediate sensorimotor adaptation to novel environments engage neural circuits that represent the required movement in joint-based or muscle-based coordinate systems. We sought to establish the contribution of these alternative representations to the process of visuomotor adaptation. To do so we applied a visuomotor rotation during a center-out isometric torque production task that involved flexion/extension and supination/pronation at the elbow-joint complex. In separate sessions, distinct half-quadrant rotations (i.e., 45°) were applied such that adaptation could be achieved either by only rescaling the individual joint torques (i.e., the visual target and torque target remained in the same quadrant) or by additionally requiring torque reversal at a contributing joint (i.e., the visual target and torque target were in different quadrants). Analysis of the time course of directional errors revealed that the degree of adaptation was lower (by ∼20%) when reversals in the direction of joint torques were required. It has been established previously that in this task space, a transition between supination and pronation requires the engagement of a different set of muscle synergists, whereas in a transition between flexion and extension no such change is required. The additional observation that the initial level of adaptation was lower and the subsequent aftereffects were smaller, for trials that involved a pronation–supination transition than for those that involved a flexion–extension transition, supports the conclusion that the process of adaptation engaged, at least in part, neural circuits that represent the required motor output in a muscle-based coordinate system.
Modulation of Low-Frequency-Induced Synaptic Depression in the Developing CA3–CA1 Hippocampal Synapses by NMDA and Metabotropic Glutamate Receptor Activation
Authors: Strandberg Joakim , Wasling Pontus , Gustafsson Bengt
Published: February 2009

Brief test-pulse stimulation (0.2–0.05 Hz) of naïve (previously nonstimulated) developing hippocampal CA3–CA1 synapses leads to a substantial synaptic depression, explained by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) silencing. Using field recordings in hippocampal slices from P8 to P12 rats, we examined this depression of naïve synapses using more prolonged test-pulse stimulation as well as low-frequency (1 Hz) stimulation (LFS). We found that 900 stimuli produced depression during stimulation to ∼40% of the naïve level independent of whether test-pulse stimulation or LFS was used. This result was also observed during combined blockade of N-methyl-d-aspartate/metabotropic glutamate receptors (NMDAR/mGluRs) although the depression was smaller (to ∼55% of naïve level). Using separate blockade of either NMDARs or mGluRs, we found that this impairment of the depression resulted from the NMDAR, and not from the mGluR, blockade. In fact, during NMDAR blockade alone, depression was smaller even than that observed during combined blockade. We also found that mGluR blockade alone facilitated the LFS-induced depression. In conclusion, test-pulse stimulation produced as much depression as LFS when applied to naïve synapses even when allowing for NMDAR and mGluR activation. Our results seem in line with the notion that NMDARs and mGluRs may exert a bidirectional control on AMPA receptor recruitment to synapses.
Ras/Raf-1/MAPK Pathway Mediates Response to Tamoxifen but not Chemotherapy in Breast Cancer Patients
Authors: McGlynn Liane M. , Kirkegaard Tove , Edwards Joanne , Tovey Sian , Cameron David , Twelves Chris , Bartlett John M.S. , Cooke Timothy G.
Published: February 2009

Purpose: The expression and activation of the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway plays an important role in the development and progression of cancer, and may influence response to treatments such as tamoxifen and chemotherapy. In this study we investigated whether the expression and activation of the key components of this pathway influenced clinical outcome, to test the hypothesis that activation of the MAPK pathway drives resistance to tamoxifen and chemotherapy in women with breast cancer.

Experimental Design: Breast tumors from patients at the Glasgow Royal Infirmary and others treated within the BR9601 trial were analyzed for expression of the three Ras isoforms, total Raf-1, active and inactive forms of Raf-1 [pRaf(ser338) and pRaf(ser259), respectively], MAPK, and phospho-MAPK using an immunohistochemical approach. Analyses were done with respect to disease free-survival and overall survival.

Results: Expression and activation of the Ras pathway was associated with loss of benefit from treatment with tamoxifen but not chemotherapy. Overexpression of pRaf(ser338) was associated with shortened disease-free and overall survival time in univariate analyses. Multivariate analysis suggested pRaf(ser338) was independent of known prognostic markers in predicting outcome following tamoxifen treatment (P = 0.03).

Conclusion: This study suggests that activation of the Ras pathway predicts for poor outcome on tamoxifen but not chemotherapy, and identifies pRaf(ser338) as a potential marker of resistance to estrogen receptor–targeted therapy. In addition, it suggests that expression of pRaf(ser338) could identify patients for whom tamoxifen alone is insufficient adjuvant systemic therapy, but for whom the addition of chemotherapy may be of benefit.
Mutations and Response to Epidermal Growth Factor Receptor Inhibitors
Authors: Laurent-Puig Pierre , Lievre Astrid , Blons Hélène
Published: February 2009

Novel therapeutic agents targeting the epidermal growth factor receptor (EGFR) have improved outcomes for a subgroup of patients with colorectal, lung, head and neck, and pancreatic cancers. In these tumors, the EGFR activation turns on at least five different signaling pathways (RAS/mitogen-activated protein kinase, phospholipase C, phosphatidylinositol 3-kinase/AKT, signal transducer and activator of transcription, and SRC/FAK pathways), which are intimately interconnected, and frequent mutations involving either the receptor itself or downstream effectors have been found. Up to now, it seems that alterations at the EGFR level has major importance in EGFR tyrosine kinase inhibitor response, whereas modifications of downstream effectors could lead to treatment resistance. Furthermore, our understanding of the mechanism of the EGFR network activation provides new hypotheses on potential new anticancer drugs that may be effective.
Sphingosine Kinase 1 Is Associated with Gastric Cancer Progression and Poor Survival of Patients
Authors: Li Wen , Yu Chun-Ping , Xia Jin-tang , Zhang Ling , Weng Gui-Xiang , Zheng Hai-qing , Kong Qing-li , Hu Li-juan , Zeng Mu-Sheng , Zeng Yi-xin , Li Mengfeng , Li Jun , Song Li-Bing
Published: February 2009

Purpose: The present study was to investigate the clinical significance of sphingosine kinase 1 (SPHK1), an oncoenzyme, in the development and progression of gastric cancer.

Experimental Design: mRNA and protein levels of SPHK1 expression in normal gastric epithelial cells, gastric cancer cell lines, and paired gastric cancer lesions and the adjacent noncancerous tissues were examined using reverse transcription-PCR and Western blotting. Immunohistochemistry was employed to analyze SPHK1 expression in 175 clinicopathologically characterized gastric cancer cases. Statistical analyses were applied to derive prognostic and diagnostic associations.

Results: Levels of SPHK1 mRNA and protein were higher in gastric cancer cell lines than in normal gastric epithelial cells. SPHK1 protein level was up-regulated in gastric cancer lesions compared with that in the paired adjacent noncancerous tissues. Gastric cancer tissues from 115 of 175 (65.7%) patients revealed high level of SPHK1 protein expression in contrast to the undetectable or marginally detectable expression of SPHK1 in the adjacent noncancerous gastric tissues. Significantly different expression levels of SPHK1 were found in patients at different clinical stages (P = 0.003), T classification (P = 0.035), and M classification (P = 0.020). Patients with higher SPHK1 expression had shorter overall survival time, whereas those with lower SPHK1 expression survived longer. Further multivariate analysis suggested that SPHK1 up-regulation was an independent prognostic indicator for the disease.

Conclusions: SPHK1 protein could be a useful marker for the prognosis of gastric cancer. Further study on the potential use of SPHK1 as a therapeutic target is also warranted.
Adult Xp11 Translocation Renal Cell Carcinoma Diagnosed by Cytogenetics and Immunohistochemistry
Authors: Komai Yoshinobu , Fujiwara Mutsunori , Fujii Yasuhisa , Mukai Hiroyuki , Yonese Junji , Kawakami Satoru , Yamamoto Shinya , Migita Toshiro , Ishikawa Yuichi , Kurata Morito , Nakamura Takuro , Fukui Iwao
Published: February 2009

Purpose: To determine the incidence of Xp11 translocation renal cell carcinoma (RCC) in adult patients using cytogenetics and immunohistochemstry.

Experimental Design: Cytogenetic studies were prospectively done using tumor samples from 443 consecutive adult Japanese patients (ages 15-89 years) who underwent nephrectomy for RCC. TFE3 immunohistochemistry was done for cases in which cytogenetic results were not obtained. Clinicopathologic characteristics of Xp11 translocation RCC were examined.

Results: Mitotic cells suitable for cytogenetic analysis were obtained in 244 tumor samples (55%); among these, we identified 4 cases (1.6%) of Xp11 translocation RCC. TFE3 immunohistochemistry identified 3 positive cases (1.5%) among the remaining 199 cases. The median age of the 7 patients was 41 years (range, 15-59 years), and 15% of RCC patients (4 of 26) who were younger than ages 45 years had this type of RCC. Of the four Xp11 translocation RCC patients whose karyotypes were determined, two had an ASPL-TFE3 gene fusion. Of these 2, 1 had pulmonary metastasis at presentation, and the other developed liver metastasis 12 months after nephrectomy and died of the disease. The remaining two patients had PRCC-TFE3 and PSF-TFE3 gene fusions, respectively. Both had nodal involvement but remained disease free for 3 and 5 years, respectively, after surgical resection of lymph node metastases. Of the 3 immunohistochemically diagnosed patients, 1 had nodal metastases at presentation and died 9 months after surgery.

Conclusions: This is the first report to determine the incidence of Xp11 translocation RCC in adult patients. We found that this disease is relatively common in young adults.
Immunogenicity and Antitumor Effects of Vaccination with Peptide Vaccine +/− Granulocyte-Monocyte Colony-Stimulating Factor and/or IFN-α2b in Advanced Metastatic Melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696
Authors: Kirkwood John M. , Lee Sandra , Moschos Stergios J. , Albertini Mark R. , Michalak John C. , Sander Cindy , Whiteside Theresa , Butterfield Lisa H. , Weiner Louis
Published: February 2009

Purpose: No therapy has ever shown prolongation of survival in stage IV metastatic melanoma. The association of cytokine-induced autoimmunity with improved prognosis led us to investigate the effect of multi-epitope melanoma vaccines alone and in combination with cytokines in this Eastern Cooperative Oncology Group multicenter phase II trial.

Experimental Design: Eligible patients were required to have failed prior therapies and to be HLA-A2 positive. Three HLA class I-restricted lineage antigen epitopes were administered in a factorial 2 × 2 design. Peptide vaccine alone (arm A), or combined with granulocyte-monocyte colony-stimulating factor (GM-CSF; Immunex) 250 μg/d subcutaneously for 14 of 28 days each month (arm B), or combined with IFN-α2b (Intron A; Schering-Plough) 10 million units/m2 three times a week (arm C), or combined with both IFN-α2b and GM-CSF (arm D). The primary endpoint was immune response measured by enzyme-linked immunospot assay; secondary endpoints were clinical antitumor response, disease-free survival, and overall survival.

Results: One hundred twenty patients enrolled and 115 patients were analyzed. Immune responses to at least one melanoma antigen were observed in 26 of 75 (35%) patients with serial samples. Neither IFN-α2b nor GM-CSF significantly improved immune responses. Six objective clinical responses were documented. At a median follow-up of 25.4 months, the median overall survival of patients with vaccine immune response was significantly longer than that of patients with no immune response (21.3 versus 13.4 months; P = 0.046).

Conclusion: Immune response to vaccination correlates with prolonged survival in patients with metastatic melanoma and is not enhanced by immunomodulatory cytokines as tested in this trial.
Uncovering Growth-Suppressive MicroRNAs in Lung Cancer
Authors: Liu Xi , Sempere Lorenzo F. , Galimberti Fabrizio , Freemantle Sarah J. , Black Candice , Dragnev Konstantin H. , Ma Yan , Fiering Steven , Memoli Vincent , Li Hua , DiRenzo James , Korc Murray , Cole Charles N. , Bak Mads , Kauppinen Sakari , Dmitrovsky Ethan
Published: February 2009

Purpose: MicroRNA (miRNA) expression profiles improve classification, diagnosis, and prognostic information of malignancies, including lung cancer. This study uncovered unique growth-suppressive miRNAs in lung cancer.

Experimental Design: miRNA arrays were done on normal lung tissues and adenocarcinomas from wild-type and proteasome degradation-resistant cyclin E transgenic mice to reveal repressed miRNAs in lung cancer. Real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays validated these findings. Lung cancer cell lines were derived from each transgenic line (designated as ED-1 and ED-2 cells, respectively). Each highlighted miRNA was independently transfected into these cells. Growth-suppressive mechanisms were explored. Expression of a computationally predicted miRNA target was examined. These miRNAs were studied in a paired normal-malignant human lung tissue bank.

Results: miR-34c, miR-145, and miR-142-5p were repressed in transgenic lung cancers. Findings were confirmed by real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays. Similar miRNA profiles occurred in human normal versus malignant lung tissues. Individual overexpression of miR-34c, miR-145, and miR-142-5p in ED-1 and ED-2 cells markedly repressed cell growth. Anti-miR cotransfections antagonized this inhibition. The miR-34c target, cyclin E, was repressed by miR-34c transfection and provided a mechanism for observed growth suppression.

Conclusions: miR-34c, miR-145, and miR-142-5p were repressed in murine and human lung cancers. Transfection of each miRNA significantly repressed lung cancer cell growth. Thus, these miRNAs were growth suppressive and are proposed to exert antineoplastic effects in the lung.
High Cytotoxicity of Cisplatin Nanocapsules in Ovarian Carcinoma Cells Depends on Uptake by Caveolae-Mediated Endocytosis
Authors: Hamelers Irene H.L. , Staffhorst Rutger W.H.M. , Voortman Jarno , de Kruijff Ben , Reedijk Jan , van Bergen en Henegouwen Paul M.P. , de Kroon Anton I.P.M.
Published: February 2009

Purpose: Cisplatin nanocapsules, nanoprecipitates of cisplatin encapsulated in phospholipid bilayers, exhibit increased in vitro toxicity compared with the free drug toward a panel of human ovarian carcinoma cell lines. To elucidate the mechanism of cell killing by nanocapsules and to understand the cell line dependence of nanocapsule efficacy, the route of uptake and the intracellular fate of the nanocapsules were investigated.

Experimental Design: Intracellular platinum accumulation and cisplatin-DNA-adduct formation were measured in cell lines that differ in sensitivity to cisplatin nanocapsules. Confocal fluorescence microscopy in combination with down-regulation with small interfering RNA was used to map the route of cellular uptake of nanocapsules containing fluorescein-labeled cisplatin.

Results: In sensitive cell lines, cisplatin from nanocapsules is taken up much more efficiently than the free compound. In IGROV-1 cells, the increased platinum accumulation results in augmented cisplatin-DNA-adduct formation. Confocal fluorescence microscopy revealed that the uptake of nanocapsules is energy dependent. Colocalization with markers of early and late endosomes indicated uptake via endocytosis. Down-regulation of caveolin-1 with small interfering RNA inhibited the uptake and cytotoxic effect of nanocapsules in IGROV-1 cells. Ovarian carcinoma cells, in which the nanocapsules are less effective than in IGROV-1 cells, do not internalize the nanocapsules (OVCAR-3) or accumulate them in an endocytic compartment after clathrin-mediated endocytosis (A2780).

Conclusions: The high cytotoxicity of cisplatin nanocapsules requires caveolin-1-dependent endocytosis that is followed by release of the drug from a late endosomal/lysosomal compartment and cisplatin-DNA-adduct formation. The findings may be applied in predicting the efficacy of nanoparticulate anticancer drug delivery systems in treating different tumor types.
IL15 Can Reverse the Unresponsiveness of Wilms' Tumor Antigen-Specific CTL in Patients with Prostate Cancer
Authors: King Judy W. , Thomas Sharyn , Corsi Fabrizio , Gao Liquan , Dina Roberto , Gillmore Roopinder , Pigott Katharine , Kaisary Amir , Stauss Hans J. , Waxman Jonathan
Published: February 2009

Purpose: The Wilms' tumor antigen 1 (WT1) is overexpressed in several leukemias and solid tumors, but there is currently limited information regarding its role in prostate cancer. This study aimed to investigate WT1 expression in prostate cancer, and to determine the number and function of WT1-specific T cells in the peripheral blood of patients.

Experimental Design: Immunohistochemistry was used to assess WT1 expression in cancer tissues. Human leukocyte antigen A2 (HLA-A2) tetramers served to detect WT1-specific T cells, and peptide-specific stimulation was used to assess T-cell function in vitro.

Results: Immunohistochemistry of tissue arrays comprising 36 cancer and 8 normal prostate samples revealed nuclear WT1 staining in 39% of cancer samples, but not in normal prostate tissues. Tetramer analysis revealed a low frequency of WT1-specific T cells in 20 of 38 HLA-A2–positive patients. In vitro stimulation with WT1 peptide plus interleukin 2(IL2) and interleukin 7 (IL7) did not lead to an accumulation of WT1-specific T cells in any of the patient samples, although all patients were able to generate T-cell responses against Melan-A/MART1 control peptide. Stimulation with WT1 peptide in the presence of interleukin 15 (IL15), a cytokine that was shown to reverse tolerance of murine tumor-specific T cells, was able to restore the expansion and IFNγ production of WT1-specific T cells in a subgroup of prostate cancer patients.

Conclusion: The observation that IL15 can restore the function of WT1-specific T cells that were unresponsive to IL2 has implications for vaccination and immunotherapeutic strategies that aim to enhance WT1-specific T cell immunity in patients.
A Phase I Trial to Determine the Safety, Tolerability, and Maximum Tolerated Dose of Deforolimus in Patients with Advanced Malignancies
Authors: Hartford Christine M. , Desai Apurva A. , Janisch Linda , Karrison Theodore , Rivera Victor M. , Berk Lori , Loewy John W. , Kindler Hedy , Stadler Walter M. , Knowles Heather L. , Bedrosian Camille , Ratain Mark J.
Published: February 2009

Purpose: This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied.

Experimental Design: Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated the drug without significant toxicities.

Results: Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response, 21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC (P = 0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy and change in tumor size (r = −0.38; P = 0.029).

Conclusions: Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be studied further.
COL4A1
Is Associated With Arterial Stiffness by Genome-Wide Association Scan
Authors: Tarasov Kirill V. , Sanna Serena , Scuteri Angelo , Strait James B. , Orrù Marco , Parsa Afshin , Lin Ping-I , Maschio Andrea , Lai Sandra , Piras Maria Grazia , Masala Marco , Tanaka Toshiko , Post Wendy , O'Connell Jeffrey R. , Schlessinger David , Cao Antonio , Nagaraja Ramaiah , Mitchell Braxton D. , Abecasis Gonçalo R. , Shuldiner Alan R. , Uda Manuela , Lakatta Edward G. , Najjar Samer S.
Published: February 2009

Background—

Pulse wave velocity (PWV), a noninvasive index of central arterial stiffness, is a potent predictor of cardiovascular mortality and morbidity. Heritability and linkage studies have pointed toward a genetic component affecting PWV. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with PWV.

Methods and Results—

The study cohort included participants from the SardiNIA study for whom PWV measures were available. Genotyping was performed in 4221 individuals, using either the Affymetrix 500K or the Affymetrix 10K mapping array sets (with imputation of the missing genotypes). Associations with PWV were evaluated using an additive genetic model that included age, age
2
, and sex as covariates. The findings were tested for replication in an independent internal Sardinian cohort of 1828 individuals, using a custom chip designed to include the top 43 nonredundant SNPs associated with PWV. Of the loci that were tested for association with PWV, the nonsynonymous SNP rs3742207 in the
COL4A1
gene on chromosome 13 and SNP rs1495448 in the
MAGI1
gene on chromosome 3 were successfully replicated (
P
=7.08�10
−7
and
P
=1.06�10
−5
, respectively, for the combined analyses). The association between rs3742207 and PWV was also successfully replicated (
P
=0.02) in an independent population, the Old-Order Amish, leading to an overall
P
=5.16�10
−8
.

Conclusions—

A genome-wide association study identified a SNP in the
COL4A1
gene that was significantly associated with PWV in 2 populations. Collagen type 4 is the major structural component of basement membranes, suggesting that previously unrecognized cell-matrix interactions may exert an important role in regulating arterial stiffness.
A Buried Past: The Tomb Inscription (Muzhiming) and Official Biographies of Wang Chuzhi (863-923)
Authors: Schottenhammer Angela
Published: February 2009

The present article investigates the tomb inscription of Wang Chuzhi (863-923), a military governor whose career spanned the end of the Tang and the beginning of the Five Dynasties. By comparing the inscription with representations of the deceased in official sources, the article reveals that the tomb inscription presents a critical attitude toward the moral standards of conventional historiography, and demonstrates a shifting moral geography in the works of Song historians. This new standard increasingly excluded nomadic peoples from the newly imagined political body, and excluded with them the pragmatic diplomacy that had characterized the politics of the Five Dynasties. Cet article analyse l'inscription funéraire de Wang Chuzhi (863-923). Ce gouverneur militaire vécut à la fin des Tang et au début de la période des Cinq Dynasties. La comparaison de l'inscription à diverses représentations du défunt contenues dans les sources officielles montre la manière dont l'auteur de l'inscription critique les standards moraux de l'historiographie officielle. Elle montre aussi le cadre géographique mouvant dans lequel s'appliquait la morale Song: les populations nomades étaient de plus en plus exclues du corps politique tel qu'il était alors imaginé; la diplomatie pragmatique qui avait dominé la période des Cinq Dynasties était abandonnée.
Wards of Words: Textual Geographies and Urban Space in Song-Dynasty Luoyang, 960-1127
Authors: de Pee Christian
Published: February 2009

The conventions of inherited genres of literary composition reorganized the essential horizontality of eleventh-century urban space into vertical, hierarchical geographies that excluded markets, stores, alleyways, and commoners. Poems and inscriptions composed in Luoyang render detailed walks within gardens and outside the city walls, but not urban itineraries. Only the unusual events of miracle tales and the unusual time of the peony season disrupt conventional textual geographies and render visible commoners and commerce in a horizontal, vernacular urban space. Archaeological remains further demonstrate the limiting conventions of transmitted texts. Les conventions des genres littéraires traditionnels substituent à l'essentielle horizontalité de l'espace urbain du XIe siècle des géographies verticales et hiérarchiques qui excluent les marchés, les magasins, les ruelles, et le menu peuple. Les poèmes et les inscriptions composées en Luoyang décrivent d'innombrables promenades dans les jardins et en dehors des murs, mais elles omettent les itinéraires urbains. Seuls les événements extraordinaires des contes miraculeux et le temps exceptionnel de la saison des pivoines dérangent les géographies textuelles traditionnelles et rendent visible le menu peuple et le commerce dans un espace urbain qui devient horizontal et informel. Les vestiges archéologiques confirment le caractère restrictif des conventions textuelles transmises par la tradition.
The Use of the Terms αγνεια, παρενια, σωροσυνη, and εγκρατεια in the Symposium of Methodius of Olympus
Authors: Zorzi Benedetta
Published: February 2009

In order to pinpoint the position of Methodius of Olympus in the debate with the encratist movement during the first centuries A.D. the usual terminology needs to be defined. Only then will it be possible to recognise Methodius' originality, which manifests itself in two respects: the body's natural ability to comply with the Spirit and, on the other hand, the extension of the concept of 'chastity' to the spiritual realm. The paper contains a systematic reading of the discourses of Methodius' Symposium, focusing on the semantics of the four relevant terms mentioned in the title of the paper.
Dietary shift in benthivorous cichlids after the ecological changes in Lake Victoria
Authors: Kishe-Machumu Mary , Witte Frans , Wanink Jan
Published: February 2009

Cichlid fishes of Lake Victoria are well known for their trophic specializations. In our study area, the sub-littoral waters of the Mwanza Gulf (Tanzania), at least 12 trophic groups coexisted in the 1970s. After the Nile perch upsurge and eutrophication in the 1980s, most cichlids disappeared from the area. During the 1990s, heavy exploitation of Nile perch reduced the abundance of this predator. Subsequently, some cichlid species, mainly zooplanktivores and small benthivores, recovered. To establish their ecological role in the changed environment, among other factors we studied their diet. Stomach contents of fish caught before and after the ecological changes were compared. The small benthivores shifted from a diet dominated by detritus and phytoplankton, supplemented with small quantities of midge larvae and zooplankton, to a diet of invertebrate preys of larger sizes. Currently, the diet includes zooplankton, midge larvae, shrimps and molluscs, and a very small amount of detritus and phytoplankton. Apparently, the recovering benthivores have a more carnivorous than a herbivorous diet. Concomitantly, the ratio of intestine length to standard length of the benthivores decreased with 30% and the average stomach fullness decreased as well. The observed dietary shifts may be due to (1) the changed availability of food types and a decline of the nutritious quality of detritus and phytoplankton due to the strong increase of cyanobacteria in the lake, (2) the decline of the former trophic specialists, and (3) the reduced water clarity. The diet of the former detritivores is currently very similar to that of the zooplanktivores. Consequently, if diet plays a role in the relatively slow recovery of the small benthivores compared to the zooplanktivores, this would only hold if they are relatively poorly adapted to their new diet.
Identification of benthic invertebrate and diatom indicator taxa that distinguish different stream types as well as degraded from reference conditions in Luxembourg
Authors: Dohet Alain , Ector Luc , Cauchie Henry-Michel , Hoffmann Lucien
Published: February 2009

The main objective of the Water Framework Directive (WFD) is to achieve good ecological status for surface waters in Europe by 2015. The ecological status has to be defined based on near-natural reference conditions. Benthic invertebrates and diatoms are among the key biological elements recommended by the Directive to assess ecological quality of water bodies. The purpose of this study is to identify species associations of these biological elements that are characteristic of the different stream types occurring in Luxembourg and that distinguish degraded from reference conditions. In general, the results reveal that diatoms and invertebrates can be considered as complementary indicators with more diatom species being characteristic of small size stream types and more benthic invertebrate species being associated with larger stream types. Among invertebrates, Trichoptera, Hydrachnidia, Ephemeroptera and Diptera show high affinities for most stream types. Plecoptera, Oligochaeta appear as useful indicators for some particular types. If only reference sites are selected (all river types considered), the number of indicator species drops from 55 to 24 for diatoms and from 81 to 48 for benthic invertebrates. Moreover, for the larger stream type, no reference site was found at all. This trend is likely to be a consequence of the multiple anthropogenic pressures that have affected large parts of European lowland rivers for decades. Our results suggest that Trichoptera, Hydrachnidia, Diptera, Ephemeroptera and Oligochaeta could be considered as best candidate groups for a tiered-taxonomic resolution approach where only taxa which have narrow and specific ecological requirements would be identified to finer levels. In Central Europe, however, since taxonomic soundness and easy recognition are required, only Trichoptera and Ephemeroptera are the groups to be recommended at the present time.
State Responsibility and the Primary-Secondary Rules Terminology – The Role of Language for an Understanding of the International Legal System
Authors: Linderfalk Ulf
Published: February 2009

In the international legal literature, it is commonplace to talk about the law of state responsibility as secondary rules of law. The terminology emphasises that in some way or another the law of state responsibility is different from other rules of the international legal system – what international legal scholars refer to as primary rules of law. The present essay inquires into the soundness of this language. As argued, the primary-secondary rules terminology builds on two assumptions. First, it assumes that the law of state responsibility can be described as separate from the ordinary (or primary) rules of international law. Secondly, it assumes that the two classes of rules can be described as pertaining to different stages of the judicial decision-making process. As shown in this essay, neither assumption can be defended as correct.
The Neutral Ally: The European Security and Defence Policy and the Swedish Constitution
Authors: Österdahl Inger
Published: February 2009

The Swedish defence policy has undergone a dramatic shift in recent years from focusing on defending Swedish territory to focusing on making the world a better place. The questions asked in this article relate to the Swedish constitutional regulation of the use of the Swedish armed forces and the potential impact of the European Security and Defence Policy on the interpretation of the Constitution. A fundamental revision of a policy central to the identity of the state has taken place, and the constitutional regulation as such stays intact. The old constitutional rules also function in the new defence policy environment, but new practice may entail a new interpretation. Different aspects of the change in defence policy will be weighed in relation to the existing Constitution. The Constitution sets limits to when Swedish armed forces may be sent abroad, but it also provides the opportunities. In a time of internationalisation and active use of military means to accomplish things around the world, the enabling aspect of the Constitution becomes important. The constitutional regulation accords the government and Parliament a lot of freedom, indeed unlimited freedom as long as they agree. Under the Constitution any coalition, context or cause is just.
Restless Spirits in the Land: Finding a Place in Canadian Law for Aboriginal Civil Disobedience
Authors: Milward David
Published: February 2009

This article will argue that Aboriginal use of civil disobedience should be legalised within limited circumstances. Aboriginal peoples have constitutional rights under s. 35(1) of the Constitution Act, 1982. The Supreme Court of Canada decided in Haida that if a Canadian government possesses knowledge, real or constructive, that its actions may affect Aboriginal interests that are potentially protected under s. 35(1), that government then has duties towards the Aboriginal peoples concerned. These duties can include giving prior notice of the proposed action, or even interim accommodation of the Aboriginal interests pending final resolution. If the Canadian state undertakes an action that 1) threatens harm to or interference with an Aboriginal interest and 2) in a manner that reflects a failure to uphold its obligations under Haida and 3) the action is commenced before the interim hearing contemplated by Haida can be initiated, Aboriginal peoples should be allowed to have recourse to civil disobedience to block that action. The idea is that the action reflects a failure by the state to uphold the rule of law with respect to Aboriginal rights and therefore should disentitle the state from enforcing such action through criminal prosecution.
The Roma Minority and the Utility of Human Rights
Authors: Ringelheim Julie
Published: February 2009

Given the magnitude of difficulties experienced by Roma across Europe, some scholars have come to question the utility of individual human rights, as presently guaranteed in international law, as a tool to improve their situation. However, it is important in such a discussion not to confuse problems of substance with problems of effectiveness of the rights. Furthermore, one must keep in mind the different conceptions of human rights obligations. Their relevance for such a deprived minority as the Roma, depends on whether a 'thick' – rather than a formalistic and minimalist – view of human rights is accepted, whereby public authorities are required to take action, where necessary, so as to effectively protect and fulfil the rights guaranteed.
Keeping Up with the Fashion: Human Rights and Global Public Goods
Authors: Langford Malcolm
Published: February 2009

The strategic genius of some recent development discourses lies in their appropriation or reappropriation of hegemonic ideas and practices. However, the choice of a conservative framework for progressive goals may mean that the compromise may be more than symbolic. The global public goods movement seeks to resuscitate earlier economic ideas about the economic utility of the public provision of certain goods but in this case at a supranational level. The book Towards New Global Strategies: Public Goods and Human Rights attempts to engage with the idea from a human rights perspective. While there are some notable contributions, much of the book founders on a failure to understand the different, and sometimes confused, strands of the global public goods thinking and properly engage with them from a human rights perspective. This article tries to tease out what appears to be the two diffent schools of thought of global public goods and the human rights questions that should be posed to them. Given the dominance of the economics discourse and the enduring nationalism in much international development cooperation, instrumental arguments for the utility of human rights and development should be cautiously welcomed but also carefully critiqued.
Gleanings on Jews of Greater Iran under the Sasanians: (According to the Oldest Armenian and Georgian Texts)
Authors: Shapira Dan
Published: February 2009

This paper is an unbiased investigation of two Jewish tomb inscriptions from Mc'xeta, Georgia, claimed to support the legends about the mission of St. Nino, into the broader context of the oldest Armenian and Georgian texts that mention Jews, with the emphasis on Armenian-Georgian ecclesiastical relations. The conclusion of the author is that it is impossible to use the two mentioned inscriptions as an evidence for a Georgian Jewish community in Mc'xeta in the 4th or 5th centuries.
Iranian *L, and Some Persian and Zaza Etymologies
Authors: Schwartz Martin
Published: February 2009

This paper aims to establish Proto-Iranian *l by focusing on a variety of words in (I) Persian and (II) Zaza, many of which are of intrinsic etymological interest. In addition, (III) other etymologically noteworthy Zaza words are discussed.
The Sogdian "Ancient Letters" (I, III)
Authors: Livshits Vladimir
Published: February 2009

The "Ancient Letters" is a conventional term applied to a group of Sogdian paper documents (five letters and a number of fragments) found by Aurel Stein in 1907, in the remains of a watch-tower on the Chinese frontier wall. The letters were written, most likely, in the first decades of the 4th century A.D. The "Ancient Letters" are the earliest Sogdian handwritten texts and the oldest available paper documents.The author presents the translations of the first and third letters dictated by a woman named Mēwnāi (lit. "tiger cub"), whose husband Nanaidāt (lit. "Created by goddess Nanai") had left her in Tun-huang.
Are Verbs Always What They Seem To Be?
Authors: Hewitt George
Published: February 2009

The North West Caucasian language-family is noted (notorious) for the polysynthetic nature of its verbs. If one couples this with fact (a) that morphemes typically take the shape C(V) and fact (b) that the language has a minimum of 58 consonantal phonemes (sc. in its literary dialect) and that homonymy is widespread, one might expect that, for ease of encoding/decoding, verb-forms would shew great regularity and structural transparency. On the whole, this is indeed the case. However, there are instances where analysis presents some problems.In Abkhaz the causative marker is 'r' prefixed to the verbal root (sometimes to the preverb). Since the procedure for causative formation is clearly of the synthetic type, one would expect that all verbs containing this marker would have to be transitive, and yet the verb /s-'p∫w-r-t∫t∫a-wa-jt'/ 'I smile' has only the one argument, represented by the initial fricative for the 1st person singular, and is intransitive. The verb /j-'s-kw-na-psa-jt'/ 'I came out in a rash' looks to be monovalent and yet has three arguments and is ditransitive, just like its counterpart in the unrelated but neighbouring language Georgian /(muts'uk'-εb-i) ga-m-m-(a-)q'ar-a/ 'I came out in a rash (of spots)'. From its form the Mingrelian verb /-rt-u-k/ looks to be an intransitive form (by virtue of ending in /-u-k/), and yet, if we place the verb in a sentence /si mu-s -rt-u-k/ 'What are you doing?', one might be excused for taking it to be a proto-typical transitive (cp. the exact equivalent in the sister-language Georgian /∫en ra-s∫vr-εb-i/). The paper examines a range of such apparent inconsistencies and some consequential misanalyses.