bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatty acid synthase inhibition results in a magnetic resonance–detectable drop in phosphocholine
Authors: Ross James , Najjar Amer M. , Sankaranarayanapillai Madhuri , Tong William P. , Kaluarachchi Kumaralal , Ronen Sabrina M.
Published: August 2008

Expression of fatty acid synthase (FASN), the key enzyme in de novo synthesis of long-chain fatty acids, is normally low but increases in cancer. Consequently, FASN is a novel target for cancer therapy. However, because FASN inhibitors can lead to tumor stasis rather than shrinkage, noninvasive methods for assessing FASN inhibition are needed. To this end, we combined 1H, 31P, and 13C magnetic resonance spectroscopy (MRS) (a) to monitor the metabolic consequences of FASN inhibition and (b) to identify MRS-detectable metabolic biomarkers of response. Treatment of PC-3 cells with the FASN inhibitor Orlistat for up to 48 h resulted in inhibition of FASN activity by 70%, correlating with 74% inhibition of fatty acid synthesis. Furthermore, we have determined that FASN inhibition results not only in lower phosphatidylcholine levels but also in a 59% drop in the phospholipid precursor phosphocholine (PCho). This drop resulted from inhibition in PCho synthesis as a result of a reduction in the cellular activity of its synthetic enzyme choline kinase. The drop in PCho levels following FASN inhibition was confirmed in SKOV-3 ovarian cancer cells treated with Orlistat and in MCF-7 breast cancer cells treated with Orlistat as well as cerulenin. Combining data from all treated cells, the drop in PCho significantly correlated with the drop in de novo synthesized fatty acid levels, identifying PCho as a potential noninvasive MRS-detectable biomarker of FASN inhibition in vivo. [Mol Cancer Ther 2008;7(8):2556–65]
Targeting tumor cells expressing p53 with a water-soluble inhibitor of Hdm2
Authors: Kitagaki Jirouta , Agama Keli K. , Pommier Yves , Yang Yili , Weissman Allan M.
Published: August 2008

The tumor suppressor protein p53 is a potent inducer of apoptosis in transformed cells. Hdm2 is an ubiquitin ligase (E3) that acts as a major regulator of p53 by promoting its ubiquitylation and proteasomal degradation. For this reason, inhibiting the E3 activity of Hdm2 has been proposed as a therapeutic approach for cancers expressing wild-type p53. We previously identified a family of small molecules (HLI98s, 7-nitro-10-aryl-5-deazaflavins) that inhibit the E3 activity of Hdm2, increase cellular p53, and selectively kill transformed cells expressing wild-type p53. However, issues of both potency and solubility in aqueous solution limit the utility of the HLI98s. Here, we report that a highly soluble derivative of the HLI98s, which has a 5-dimethylaminopropylamino side chain but lacks the 10-aryl group (HLI373), has greater potency than the HLI98s in stabilizing Hdm2 and p53, activating p53-dependent transcription, and inducing cell death. Furthermore, we show that HLI373 is effective in inducing apoptosis of several tumor cells lines that are sensitive to DNA-damaging agents. These results suggest that HLI373 could serve as a potential lead for developing cancer therapeutics based on inhibition of the ubiquitin ligase activity of Hdm2. [Mol Cancer Ther 2008;7(8):2445–54]
Caspase-2 functions upstream of mitochondria in endoplasmic reticulum stress-induced apoptosis by bortezomib in human myeloma cells
Authors: Gu Hongtao , Chen Xiequn , Gao Guangxun , Dong Hongjuan
Published: August 2008

Multiple myeloma is an incurable plasma cell malignancy. The 26S proteasome inhibitor, bortezomib, selectively induces apoptosis in multiple myeloma cells; however, the mechanism by which this compound acts remains unknown. Here, we, using immunoblotting analysis, observed that the expression of BiP, CHOP, and XBP-1 is up-regulated in bortezomib-induced apoptosis in human multiple myeloma cell lines NCI-H929 and RPMI-8226/S, strongly suggesting that endoplasmic reticulum (ER) stress response or the unfolded protein response (UPR), a signaling pathway activated by the accumulation of unfolded proteins within ER, is initiated. In the meantime, we also showed that bortezomib inhibited classic ER stressor brefeldin A–induced up-regulation of prosurvival UPR components BiP and XBP-1, resulting in increased induction of apoptosis in multiple myeloma cell lines, raising the possibility that bortezomib induces apoptosis of multiple myeloma cells by means of evoking the severe ER stress but disrupting the prosurvival UPR required. Using caspase inhibitors and a RNA interference approach, we finally confirmed that bortezomib-triggered apoptosis in multiple myeloma cells is dependent on caspase-2 activation, which is associated with ER stress and required for release of cytochrome c, breakdown of mitochondrial transmembrane potential, and its downstream caspase-9 activation. Taken together, these data strongly suggest that caspase-2 can serve as a proximal caspase that functions upstream of mitochondrial signaling during ER stress-induced apoptosis by bortezomib in multiple myeloma cells. [Mol Cancer Ther 2008;7(8):2298–307]
Cellular commitment to reentry into the cell cycle after stalled DNA is determined by site-specific phosphorylation of Chk1 and PTEN
Authors: Martin Sarah A. , Ouchi Toru
Published: August 2008

In this study, we show that depletion of Chk1 by small interfering RNA (siRNA) results in failure of reentry to the cell cycle after DNA replication has been stalled by exposure to hydroxyurea (HU). Casein kinase II (CKII) is degraded in these cells in a proteasome-dependent manner, resulting in decreased phosphorylation and PTEN levels. We show that phosphorylation of Chk1 at Ser317 but not at Ser345 is required for phosphorylation of PTEN at Thr383 by CKII, making cell cycle reentry after HU treatment possible. Like Chk1 depletion, loss of PTEN due to siRNA is followed by inability to return to the cell cycle following HU. In Chk1-siRNA cells, reintroduction of wild-type PTEN but not PTEN T383A restores the ability of the cell to reenter the G2-M phase of the cell cycle after stalled DNA replication. We conclude that, in response to stalled DNA replication, Chk1 is phosphorylated at Ser317 by ATR resulting in stabilization of CKII, which in turn leads to phosphorylation of PTEN at Thr383. [Mol Cancer Ther 2008;7(8):2509–16]
Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms
Authors: Shankar Sharmila , Chen Qinghe , Ganapathy Suthakar , Singh Karan P. , Srivastava Rakesh K.
Published: August 2008

Recent studies have shown that naturally occurring compounds can enhance the efficacy of chemotherapeutic drugs. The objectives of this study were to investigate the molecular mechanisms by which diallyl trisulfide (DATS) enhanced the therapeutic potential of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in prostate cancer cells in vitro and on orthotopically transplanted PC-3 prostate carcinoma in nude mice. DATS inhibited cell viability and colony formation and induced apoptosis in PC-3 and LNCaP cells. DATS enhanced the apoptosis-inducing potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Dominant-negative FADD inhibited the synergistic interaction between DATS and TRAIL on apoptosis. DATS induced the expression of DR4, DR5, Bax, Bak, Bim, Noxa, and PUMA and inhibited expression of Mcl-1, Bcl-2, Bcl-XL, survivin, XIAP, cIAP1, and cIAP2. Oral administration of DATS significantly inhibited growth of orthotopically implanted prostate carcinoma in BALB/c nude mice compared with the control group, without causing weight loss. Cotreatment of mice with DATS and TRAIL was more effective in inhibiting prostate tumor growth and inducing DR4 and DR5 expression, caspase-8 activity, and apoptosis than either agent alone. DATS inhibited angiogenesis (as measured by CD31-positive and factor VIII–positive blood vessels and hypoxia-inducible factor-1α, vascular endothelial growth factor, and interleukin-6 expression) and metastasis [matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, and MT-1 MMP expression], which were correlated with inhibition in AKT and nuclear factor-κB activation. The combination of DATS and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis than either agent alone. These data suggest that DATS can be combined with TRAIL for the prevention and/or treatment of prostate cancer. [Mol Cancer Ther 2008;7(8):2328–38]
SN52, a novel nuclear factor-κB inhibitor, blocks nuclear import of RelB:p52 dimer and sensitizes prostate cancer cells to ionizing radiation
Authors: Xu Yong , Fang Fang , St. Clair Daret K. , Sompol Pradoldej , Josson Sajni , St. Clair William H.
Published: August 2008

The activation of nuclear factor-κB (NF-κB) is thought to protect cancer cells against therapy-induced cytotoxicity. RelB, a member of the NF-κB family in the alternative pathway, is uniquely expressed at a high level in prostate cancer with high Gleason scores. Here, we show that ionizing radiation (IR) enhances nuclear import of RelB, leading to up-regulation of its target gene, manganese superoxide dismutase (MnSOD), and renders prostate cancer cells resistant to IR. To selectively block RelB nuclear import, we designed a cell-permeable SN52 peptide, a variant of the SN50 peptide that has been shown to block nuclear import of NF-κB family members in the classic pathway. Inhibition of IR-induced NF-κB activation by SN50 and SN52 was achieved by selectively interrupting the association of p50 and p52 with nuclear import factors importin-α1 and importin-β1. Importantly, SN52 seems to be more efficient for radiosensitization of prostate cancer cells at clinically relevant radiation doses and has less cytotoxicity to normal prostate epithelial cells compared with the toxicity observed with SN50. These results suggest that targeting the alternative pathway is a promising approach to selectively radiosensitize prostate cancers and that SN52 may serve as a prototype biological agent for sensitizing prostate cancers to clinically relevant doses of IR. [Mol Cancer Ther 2008;7(8):2367–76]
Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma
Authors: Longo Luigia , Platini Francesca , Scardino Anna , Alabiso Oscar , Vasapollo Giuseppe , Tessitore Luciana
Published: August 2008

Anthocyanins extracted from the berries of Phillyrea latifolia L., Pistacia lentiscus L., and Rubia peregrina L., three evergreen shrubs widely distributed in the Mediterranean area, were examined for their antioxidant and anticancer activity. The P. lentiscus anthocyanins showed the highest H2O2 and 1,1-diphenyl-2-picryl-hydrazil radical scavenging effects, indicating that these compounds can be considered as an alternative source of natural antioxidants for food and pharmaceutical products. Here, we also report a novel function of anthocyanins: the induction of autophagy, a process of subcellular turnover involved in carcinogenesis. Autophagy was characterized by the up-regulation of eIF2α, an autophagy inducer, and down-regulation of mTOR and Bcl-2, two autophagy inhibitors. This led to the enhanced expression of LC3-II, an autophagosome marker in mammals, and monodansylcadaverine incorporation into autolysosomes. Anthocyanin-induced autophagy switched to apoptosis, as shown by the activation of Bax, cytochrome c and caspase 3, terminal deoxynucleotide transferase–mediated dUTP nick-end labeling–positive fragmented nuclei, and cells with sub-G1 DNA content, which were prevented by z-VAD. Inhibition of autophagy by either 3-methyladenine or Atg5 small interfering RNA enhanced anthocyanin-triggered apoptosis. This provided evidence that autophagy functions as a survival mechanism in liver cancer cells against anthocyanin-induced apoptosis and a rationale for the use of autophagy inhibitors in combination with dietary chemopreventive agents. [Mol Cancer Ther 2008;7(8):2476–85]
Clinical Features and Functioning of Patients with Minor Depression
Authors: Howland Robert H. , Schettler Pamela J. , Rapaport Mark Hyman , Mischoulon David , Schneider Trisha , Fasiczka Amy , Delrahiem Katia , Maddux Rachel , Lightfoot Michael , Nierenberg Andrew A.
Published: August 2008

Background: The two essential features of minor depression are that it has fewer symptoms than major depression and that it is less chronic than dysthymia. This study describes the clinical features and functioning of outpatients with minor depression. Methods: Subjects with minor depression (with and without a prior history of major depression) were recruited through clinical referrals and community advertising. Assessments included the Structured Clinical Interview for DSM-IV (SCID), the 17-item Hamilton Rating Scale for Depression (HAM-D), the Inventory of Depressive Symptomatology-Self Report (IDS-SR) and Clinician Rated (IDS-C) scales, the Global Assessment of Functioning (GAF) scale, the Medical Outcomes Study 36-item Short-Form scale (MOS), and the Clinical Global Impressions Severity Scale (CGI). Data from previously published studies of major depression, minor depression, and normal controls were compared to our data set. Results: Minor depression is characterized primarily by mood and cognitive symptoms rather than vegetative symptoms; the functional impairment associated with minor depression is as severe as for major depression in several areas; minor depression occurs either independently of major depression or as a stage of illness during the long-term course of major depression, and minor depression patients with and without a history of major depression have similar levels of depressive severity and functional impairment. Conclusions: These findings support the notion that minor depression is an important clinical entity that fits within the larger spectrum of depressive disorders.
Clinical Parameters to Predict Response to Interferon in Relapsing Multiple Sclerosis
Authors: Fromont A. , Debouverie M. , Le Teuff G. , Quantin C. , Binquet C. , Moreau T.
Published: August 2008

Background: To identify clinical parameters of response to β-interferon (IFN-β) in relapsing-remitting multiple sclerosis (RRMS) from an East France cohort. Methods: Data from 2,645 patients, identified by Burgundy and Lorraine multiple sclerosis (MS) networks, were computerized by a neurologist using the European Database for MS software. Patient inclusion criteria were: clinically or laboratory-supported definite RRMS according to Poser’s diagnostic criteria and treatment with IFN-β for at least 6 months. Four criteria were chosen to predict a response to IFN-β. The first criterion was any patient who had a lower annualized relapse rate under IFN-β therapy than during the year preceding treatment; the second criterion was a lower relapse rate than during the 2 years preceding treatment. The third was any patient free of relapse during the first 2 years of IFN-β therapy. The last criterion concerned the variation in the degree of disability measured by the Disability Status Scale during the first year of treatment. Multivariate logistic regression analyses were performed. Results: 751 RRMS cases were included. A higher relapse rate in the year preceding IFN-β onset, an older age at MS onset and having a polysymptomatic onset of MS were significantly associated with a response for the first criterion. With the 3 other criteria, no parameter predicting response was identified. Conclusion: Only the relapse rate in the year before initiation of IFN-β treatment appears to be able to predict response to treatment but not the one of 2 years before.
Abdominal Surgery Performed under General Anesthesia Increases Somatostatin-Like Immunoreactivity in Human Serum
Authors: Antal Andras , Nemeth Jozsef , Szolcsányi Janos , Pozsgai Gabor , Pinter Erika
Published: August 2008

Objective: It has been established in animals that somatostatin (SST) is released from pain-activated sensory nerve endings and exerts systemic antinociceptive and anti-inflammatory actions. The aim of this study was to investigate the changes of SST-like immunoreactivity (SST-LI) in human serum before, immediately after and 2 h after surgical operations. Methods: 25 patients were enrolled in the study. Laparoscopic cholecystectomy, abdominal wall hernia or inguinal hernia operations were performed under combined anesthesia. A 5-ml blood sample was drawn from each patient, the blood was centrifuged and the serum frozen. SST-LI was determined from the defrosted samples by radioimmunoassay. Results: Abdominal surgical operationsinduced a significant increase of SST-LI in the serum. 2 h later it was restored in the cases of laparoscopic interventions but still remained elevated after hernia surgeries. Conclusions: In this human study we showed for the first time that surgical interventions elevate the endogenous SST-LI in human serum. It is assumed that the released SST is derived from the activated sensory nerves. Since antinociceptive and anti-inflammatory effects of neural SST have already been established in laboratory animals, we presume that this endogenous protective mechanism also operates in humans.
Timing-Dependent Effects of Restraint Stress on Eosinophilic Airway Inflammation in Mice
Authors: Kumlien Georén S. , Olgart Höglund C. , Tcacencu I. , Wikström A.-C. , Stierna P.
Published: August 2008

Background: Chronicstress has been proposed to aggravate allergic inflammation, whereas acute stress may have functional beneficial effects. The aim of this study was to investigate the influence of timing of single short restraint stress (RST) in a model of eosinophilic airway inflammation. Methods: The airways of ovalbumin (OVA)-sensitized mice were exposed to an intranasal OVA challenge. RST was applied in two different ways; either 2 h before (pre-stress) or after (post-stress) the OVA challenge, respectively, or as a combination of stress before and after (double-stress) the OVA challenge. One group of mice was also treated with metyrapone (ME) prior to a pre-stress challenge. The inflammatory cell response was evaluated in bronchoalveolar lavage fluid (BALF), lung and nasal tissue, as well as bone marrow. Result: RST applied prior to the OVA challenge (pre-stress) inhibited OVA-induced airway inflammation in BALF and lung tissue, and reduced nasal histopathology compared to unstressed mice. Given as post-stress or double-stress, RST did not affect the inflammation in BALF, lungs or nasal tissue. Pre-treatment with ME prevented the pre-challenge stress evoked decrease in inflammation in BALF and lungs. Conclusion: Effects of RST on eosinophilic airway inflammation appear to be strongly dependent on timing and, as could be judged from the ME inhibition pattern, also corticosterone dependent. Hypothalamic-pituitary-adrenal axis activation probably influences eosinophilic inflammation through specific sequences of compartmental activation and thereby timing effects are evident on cellular recruitment pattern during the allergic reaction.
A Multicenter, Phase I Dose-Escalating Study of Docetaxel, Cisplatin and S-1 for Advanced Gastric Cancer (KDOG0601)
Authors: Nakayama Norisuke , Koizumi Wasaburo , Sasaki Tohru , Higuchi Katsuhiko , Tanabe Satoshi , Nishimura Ken , Katada Chikatoshi , Nakatani Kento , Takagi Seiichi , Saigenji Katsunori
Published: August 2008

Objective: This dose-escalation study of a combination of docetaxel, cisplatin and S-1 investigated the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), recommended dose (RD) and antitumor activity in advanced gastric cancer. Patients and Methods: Patients received docetaxel (40 mg/m2), cisplatin (DIV on day 1) and S-1 (40 mg/m2 p.o., twice daily, on days 1–14 every 28 days). The starting dose of cisplatin was 60 mg/m2 (level 1); the dose was escalated to 70 (level 2) and 80 mg/m2 (level 3) in a stepwise fashion. Results: Fourteen patients were enrolled. The MTD of cisplatin was 80 mg/m2 (level 3). DLT was grade 3 diarrhea, febrile neutropenia and delayed resumption of treatment. The RD of cisplatin was considered to be 70 mg/m2 (level 2). DLT was liver dysfunction, occurring in only 1 patient at level 2. The response rate was 69.2% (9/13). Conclusions: For combined treatment with docetaxel, cisplatin and S-1 in patients with advanced gastric cancer, RD were docetaxel 40 mg/m2, cisplatin 70 mg/m2 and S-1 80 mg/m2/day. This regimen yields a high rate of tumor response and can be administered safely. Phase II studies of this regimen are under way.
Stimulation of Proliferation of U138-MG Glioblastoma Cells by Gastrin-Releasing Peptide in Combination with Agents That Enhance cAMP Signaling
Authors: Farias Caroline Brunetto , Lima Rodrigo Cruz , Lima Luciana Otero , Flores Debora Gazzana , Meurer Luise , Brunetto Algemir Lunardi , Schwartsmann Gilberto , Roesler Rafael
Published: August 2008

Increasing evidence indicates that gastrin-releasing peptide (GRP) acts as an autocrine growth factor for brain tumors. However, it remains unclear whether the cAMP/protein kinase A (PKA) signaling pathway plays a role in mediating the mitogenic effects of GRP. We show here that GRP combined with agents that stimulate the cAMP/PKA pathway promotes proliferation of human gliobastoma cells. Treatment with GRP combined with the adenylyl cyclase activator forskolin, the cAMP analog 8-Br-cAMP or the phosphodiesterase type IV inhibitor rolipram increased proliferation of U138-MG cells in vitro measured by MTT assay. None of the compounds had an effect when given alone. GRP receptor (GRPR) mRNA and protein expression in U138-MG cells was detected by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. The results suggest that GRP and the GRPR interact with the cAMP/PKA signaling pathway in stimulating cancer cell proliferation.
Mechanisms Underlying Rate-Dependent Remodeling of Transient Outward Potassium Current in Canine Ventricular Myocytes
Authors: Xiao Ling , Coutu Pierre , Villeneuve Louis R. , Tadevosyan Artavazd , Maguy Ange , Le Bouter Sabrina , Allen Bruce G. , Nattel Stanley
Published: August 2008

Transient outward K+current (Ito) downregulation following sustained tachycardia in vivo is usually attributed to tachycardiomyopathy. This study assessed potential direct rate regulation of cardiacItoand underlying mechanisms. Cultured adult canine left ventricular cardiomyocytes (37°C) were paced continuously at 1 or 3 Hz for 24 hours.Itowas recorded with whole-cell patch clamp. The 3-Hz pacing reducedItoby 44% (P<0.01). Kv4.3 mRNA and protein expression were significantly reduced (by ≈30% and ≈40%, respectively) in 3-Hz paced cells relative to 1-Hz cells, but KChIP2 expression was unchanged. Prevention of Ca2+loading with nimodipine or calmodulin inhibition with W-7, A-7, or W-13 eliminated 3-Hz pacing-inducedItodownregulation, whereas downregulation was preserved in the presence of valsartan. Inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK)II with KN93, or calcineurin with cyclosporin A, also preventedItodownregulation. CaMKII-mediated phospholamban phosphorylation at threonine 17 was increased in 3-Hz paced cells, compatible with enhanced CaMKII activity, with functional significance suggested by acceleration of the Ca2+itransient decay time constant (Indo 1-acetoxymethyl ester microfluorescence). Total phospholamban expression was unchanged, as was expression of Na+/Ca2+exchange and sarcoplasmic reticulum Ca2+-ATPase proteins. Nuclear localization of the calcineurin-regulated nuclear factor of activated T cells (NFAT)c3 was increased in 3-Hz paced cells compared to 1-Hz (immunohistochemistry, immunoblot). INCA-6 inhibition of NFAT preventedItoreduction in 3-Hz paced cells. Calcineurin activity increased after 6 hours of 3-Hz pacing. CaMKII inhibition prevented calcineurin activation and NFATc3 nuclear translocation with 3-Hz pacing. We conclude that tachycardia downregulatesItoexpression, with the Ca2+/calmodulin-dependent CaMKII and calcineurin/NFAT systems playing key Ca2+-sensing and signal-transducing roles in rate-dependentItocontrol.
Increased Endothelial Mitogen-Activated Protein Kinase Phosphatase-1 Expression Suppresses Proinflammatory Activation at Sites That Are Resistant to Atherosclerosis
Authors: Zakkar Mustafa , Chaudhury Hera , Sandvik Gunhild , Enesa Karine , Luong Le Anh , Cuhlmann Simon , Mason Justin C. , Krams Rob , Clark Andrew R. , Haskard Dorian O. , Evans Paul C.
Published: August 2008

Atherosclerosis is a chronic inflammatory disease of arteries. It is triggered by proinflammatory mediators which induce adhesion molecules (eg, vascular cell adhesion molecule [VCAM]-1) in endothelial cells (ECs) by activating p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases by phosphorylation. Blood flow influences atherosclerosis by exerting shear stress (mechanical drag) on the inner surface of arteries, a force that alters endothelial physiology. Regions of the arterial tree exposed to high shear are protected from endothelial activation, inflammation, and atherosclerosis, whereas regions exposed to low or oscillatory shear are susceptible. We examined whether MAP kinase phosphatase (MKP)-1, a negative regulator of p38 and JNK, mediates the antiinflammatory effects of shear stress. We observed that expression of MKP-1 in cultured ECs was elevated by shear stress, whereas the expression of VCAM-1 was reduced. MKP-1 induction was shown to be necessary for the antiinflammatory effects of shear stress because gene silencing of MKP-1 restored VCAM-1 expression in sheared ECs. Immunostaining revealed that MKP-1 is preferentially expressed by ECs in a high-shear, protected region of the mouse aorta and is necessary for suppression of EC activation at this site, because p38 activation and VCAM-1 expression was enhanced by genetic deletion of MKP-1. We conclude that MKP-1 induction is required for the antiinflammatory effects of shear stress. Thus, our findings reveal a novel molecular mechanism contributing to the spatial distribution of vascular inflammation and atherosclerosis.
Favorable Trends in the Incidence and Outcome in Stroke in Nondiabetic and Diabetic Subjects
Authors: Rautio Aslak , Eliasson Mats , Stegmayr Birgitta
Published: August 2008

Background and Purpose—

Several studies indicate a declining case-fatality and mortality in stroke. Little is known about time trends in stroke for subjects with diabetes. The purpose of this study was to compare time trends in incidence, case-fatality and mortality for stroke patients with or without diabetes.

Methods—

This study was based on the Northern Sweden MONICA Project Stroke registry during 1985 to 2003. 15 382 patients, aged 35 to 74 years, were included in the study. 11 605 had a first-ever stroke and 3777 had a recurrent stroke. In both men and women previously diagnosed diabetes was found in 22.8%.

Results—

The incidence of stroke was 5 and 8 times higher in diabetic subjects than in nondiabetics, in men and women, respectively. Incidence of first-ever stroke decreased for nondiabetic men, probability value <0.001, and for diabetic women, probability value=0.012. Recurrent stroke incidence declined highly significant, probability value <0.001, in all but diabetic men. For diabetic women, the decrease in incidence in first and recurrent stroke was significantly greater than in nondiabetic women. Case-fatality and mortality in stroke declined for all groups except diabetic women with first-ever stroke. The time trends in case fatality and mortality did not differ significantly between nondiabetic and diabetic patients.

Conclusion—

The incidence of stroke declined in both nondiabetic and diabetic subjects except for diabetic men and for nondiabetic women with first-ever stroke. Case-fatality in first-ever stroke declined for all but diabetic women. This led to a decreased mortality over the 19-year period for both groups. This is the first time that the decline in stroke incidence is reported in this MONICA population.
Soluble CD36 in Plasma Is Increased in Patients With Symptomatic Atherosclerotic Carotid Plaques and Is Related to Plaque Instability
Authors: Handberg Aase , Skjelland Mona , Michelsen Annika E. , Sagen Ellen Lund , Krohg-Sørensen Kirsten , Russell David , Dahl Arve , Ueland Thor , Øie Erik , Aukrust Pål , Halvorsen Bente
Published: August 2008

Background and Purpose—

The risk for cardiovascular events is related to the composition and stability of an atherosclerotic plaque driven by inflammation and deposition of lipids. Scavenger receptors are a family of cell surface receptors involved in lipid uptake and inflammation. Recently, we found that soluble CD36 is increased in plasma from patients with diabetes strongly correlated with insulin resistance.

Methods—

We tested whether soluble CD36 is a marker of plaque stability in patients with high-grade internal carotid stenoses (n=62). The patients were classified according to plaque symptomatology and plaque echogenicity on ultrasound examination.

Results—

When patients were divided into 3 groups according to the latest clinical symptoms from plaques (ie, symptoms within the last 2 months [n=16], symptoms within the last 2 to 6 months [n=15], or asymptomatic [n=31]), the former group had significantly raised plasma levels of soluble CD36 as compared with the other 2 groups. In contrast, we found no differences in plasma levels of C-reactive protein, β-thromboglobulin, lipid parameters, or HbA1C between these groups. The patients with echolucent carotid plaques (n=20) tended to have higher soluble CD36 levels in plasma compared with those with echogenic/heterogenic plaque (n=39;
P
=0.087). By immunohistochemistry, CD36 was localized to macrophages-rich area of intima within the atherosclerotic lesion.

Conclusion—

We propose that sCD36 may be a marker of plaque instability and symptomatic carotid atherosclerosis, possibly at least partly as a result of CD36 release to the circulation from the foam cells within the atherosclerotic lesion.
Rapidly Increased Neuronal Mitochondrial Biogenesis After Hypoxic-Ischemic Brain Injury
Authors: Yin Wei , Signore Armando P. , Iwai Masanori , Cao Guodong , Gao Yanqin , Chen Jun
Published: August 2008

Background and Purpose—

Mitochondrial biogenesis is regulated through the coordinated actions of both nuclear and mitochondrial genomes to ensure that the organelles are replenished on a regular basis. This highly regulated process has been well defined in skeletal and heart muscle, but its role in neuronal cells, particularly when under stress or injury, is not well understood. In this study, we report for the first time rapidly increased mitochondrial biogenesis in a rat model of neonatal hypoxic/ischemic brain injury (H-I).

Methods—

Postnatal day 7 rats were subjected to H-I induced by unilateral carotid artery ligation followed by 2.5 hours of hypoxia. The relative amount of brain mitochondrial DNA (mtDNA) was measured semiquantitatively using long fragment PCR at various time points after H-I. HSP60 and COXIV proteins were detected by Western blot. Expression of three genes critical for the transcriptional regulation of mitochondrial biogenesis, peroxisome proliferator-activated receptor coactivator-1 (PGC-1), nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM), were examined by Western blot and RT-PCR.

Results—

Brain mtDNA content was markedly increased 6 hours after H-I, and continued to increase up to 24 hours after H-I. Paralleling the temporal change in mtDNA content, mitochondrial number and proteins HSP60 and COXIV, and citrate synthase activity were increased in neurons in the cortical infarct border zone after H-I. Moreover, cortical expression of NRF-1 and TFAM were increased 6 to 24 hours after H-I, whereas PGC-1 was not changed.

Conclusions—

Neonatal H-I brain injury rapidly induces mitochondrial biogenesis, which may constitute a novel component of the endogenous repair mechanisms of the brain.
Impact of Fever on Outcome in Patients With Stroke and Neurologic Injury
Authors: Greer David M. , Funk Susan E. , Reaven Nancy L. , Ouzounelli Myrsini , Uman Gwen C.
Published: August 2008

Background and Purpose—

Many studies associate fever with poor outcome in patients with neurological injury, but this relationship is blurred by divergence in populations and outcome measures. We sought to incorporate all recent scholarship addressing fever in brain-injured patients into a comprehensive meta-analysis to evaluate disparate clinical findings.

Methods—

We conducted a Medline search for articles since January 1, 1995 (in English with abstracts, in humans) and hand searches of references in bibliographies and review articles. Search terms covered stroke, neurological injury, thermoregulation, fever, and cooling. A total of 1139 citations were identified; we retained 39 studies with 67 tested hypotheses contrasting outcomes of fever/higher body temperature and normothermia/lower body temperature in patients with neurological injury covering 14431 subjects. A separate meta-analysis was performed for each of 7 outcome measures. Significance was evaluated with Zc developed from probability values or t values. Correlational effect size,
r
(es)
, was calculated for each study and used to derive Cohen’s d unbiased combined effect size and relative risk.

Results—

Fever or higher body temperature was significantly associated with worse outcome in every measure studied. Relative risk of worse outcome with fever was: mortality, 1.5; Glasgow Outcome Scale, 1.3; Barthel Index, 1.9; modified Rankin Scale, 2.2; Canadian Stroke Scale, 1.4; intensive care length of stay, 2.8; and hospital length of stay, 3.2.

Conclusions—

In the pooled analyses covering 14431 patients with stroke and other brain injuries, fever is consistently associated with worse outcomes across multiple outcome measures.
Energy Insecurity and Military Misadventures in the Persian Gulf Region
Authors: Singh K.R.
Published: August 2008

The article seeks to analyze the policy of USA as a self-proclaimed leader of a coalition representing the interest of the North as also its allies and supporters in the South, specially in the context of increasing sense of energy insecurity. This insecurity is caused by a combination of factors like the declining reserves in the North, continued reliance upon oil and gas for commercial energy, and the feeling that not only ‘rogue’ regimes but also non-state actors pose a threat to free flow of energy at affordable price.

That sense of increasing insecurity has prompted the US-led coalition to seek to militarily dominate a substantial part of the oil and gas reserves of the Gulf region, especially after 2003. Of late, steps have also been contemplated to force these states to open their oil and gas sector to oil majors of the North. These policies are likely to be resented, especially at the popular level, in this sensitive region. It remains to be seen whether the policy of dominating the Gulf and its energy resources by stationing large military force will succeed or further add to the sense of insecurity.
Constructing Tests of Cognitive Abilities for Schooled and Unschooled Children
Authors: Alcock K.J. , Holding P.A. , Mung'ala-Odera V. , Newton C.R.J.C.
Published: August 2008

It is frequently necessary to assess children with little or no schooling to determine their level of cognitive functioning, especially in developing countries. It is not possible, however, to assume that assessments will hold equal validity for children with and without the experience of schooling. The authors, therefore, set out to create a battery of tests suitable for both schooled and unschooled children. They assessed 973 schooled and 645 unschooled children in rural coastal Kenya using culturally adapted cognitive tests. Significant effects of age and schooling were found on all tests. On some tests (verbal knowledge, speeded figure matching, and pattern copying), unschooled children did not improve as much with age as schooled children. The effects of length of exposure to schooling and of age were greater than that of initial enrollment in school. The authors conclude that it is possible to assess unschooled children, but test batteries must be carefully constructed and standardized.
Individualism, Masculinity, and the Sources of Organizational Commitment
Authors: Gelade Garry A. , Dobson Paul , Auer Katharina
Published: August 2008

The authors examine the dependence of organizational commitment on satisfaction with job characteristics that are valued differently in 29 nations. Evidence is found for the moderating effects of national culture. Satisfaction with job characteristics that are highly valued in individualistic cultures has an increasingly strong effect on commitment as national individualism increases, while satisfaction with collectivist job characteristics has an increasingly weaker effect. Similarly, satisfaction with job characteristics that are highly valued in masculine cultures has an increasingly strong effect on commitment as national masculinity increases, while satisfaction with feminine job characteristics has an increasingly weaker effect. These findings show that the sources of organizational commitment are culturally conditioned and that their effects are predictable from Hofstede's value dimensions. The authors discuss the practical implications of these findings and suggest that cultural differences in the psychological contract may also affect the relationships between job satisfaction and commitment.
East—West Differences in Attributions for Company Performance
Authors: Hooghiemstra Reggy
Published: August 2008

Prior cross-cultural studies indicate that the self-serving attributional bias is more prevalent in Western cultures than in Eastern cultures. There is, however, a dearth of research looking into cross-cultural differences in attributional patterns that is based on publicly available archival data. This study tries to fill that lacuna. It reports the results based on a content analysis of corporate annual reports from U.S. and Japanese companies. The results reported in this study demonstrate that cross-cultural differences found in experimental settings are not necessarily observed in naturalistic settings. Specifically, this study reveals that both U.S. as well as Japanese companies explain company results in a self-serving fashion. Overall, the results support the notion that the nature of the relationship affects the extent to which cross-cultural differences in attributional patterns emerge.
Technology and Institutions
Authors: Lejano Raul P.
Published: August 2008

GIS (Geographic Information Systems) has captured planning practice to an unprecedented degree, and this article on how it reconfigures and is configured by institutional context. The author inquires into GIS as a technology for incorporating knowledge into institutional use and includes five propositions: (1) GIS's efficiencies in data processing allows it unprecedented facility and scope of analysis, (2) its use increases alienation, (3) its mimetic language furthers its role in planning, (4) its logic appears rational—purposive, but it conceals an underlying normative logic, and (5) its most profound effect is on the mapper, and the alienating and normative character of GIS necessitate new modes of “social ground-truthing.” The author studies the southeast Los Angeles (SELA) initiatives to demonstrate these propositions. This article compares two studies: one GIS-based, and the other based on participatory action research and discusses how GIS might be recontextualized into a technology for liberating democratizing processes.
The Religionspolitik of Emperor Ferdinand I (1521—1564): Tyrol1 and the Holy Roman Empire
Authors: Chisholm M.A.
Published: August 2008

The present study aims to settle a long-standing historiographical disagreement: where historians of the Habsburg dynasty have traditionally seen Emperor Ferdinand I as a Catholic moderate, those of the Tyrol have traditionally viewed him as a Catholic zealot. On the basis of original archival research, it argues in favour of the former interpretation. Though Ferdinand officially condemned Lutheranism, he tacitly tolerated the religion, whether in the Tyrol or elsewhere in Central Europe. To his way of thinking, religious co-existence was not an end in itself, but rather a temporary expedient pending the reunion of Catholicism, Utraquism and Lutheranism under the umbrella of a reformed universal Church. This interpretation follows from a perception of the Empire as a still vital political organism; thus, more than any one territory, the Reformation was a struggle over the religion of the Empire. This paper is divided into three parts. The first looks at the Tyrolean Reformation as a historical problem. The second offers a close case study of Ferdinand's Religionspolitik in the Tyrol. The third centres on Ferdinand's Religionspolitik in Germany and Bohemia.
Role of advance directives in palliative care units: a prospective study
Authors: Pautex S , Herrmann FR , Zulian GB
Published: August 2008

Advance directives (ADs) might be useful in achieving improved communication and satisfaction with decision making at the end-of-life. Our aims were to better characterise patients with advanced oncological disease who decided to complete ADs and to measure the effect of ADs completion on the satisfaction level with end-of-life care from both patients and their relatives. A prospective study was conducted in three palliative care units. Patients with advanced cancer were included if they met the following criteria: an estimated life expectancy of <6 months, fluency in French, Mini Mental State Examination >20 and not yet completed ADs. All the patients received information about ADs and decided whether to complete ADs or not. The level of satisfaction with involvement in the decision process concerning end-of-life care was assessed by means of a written questionnaire. In all, 53 of 228 patients were included, and 12 decided to complete ADs. Patients who completed ADs had statistically less depression one week after inclusion ( P = 0.030), had a lower anxiety score on the second week and had a lower depression score on the third week. There was a trend towards a higher satisfaction level with the involvement of the patients in end-of-life care for those completing ADs ( P = 0.878). In conclusion, each patient with an advanced progressive disease should be informed about ADs and be encouraged to complete the ADs with the aim to ease many fears as well as to improve communication.
Enhanced tolerability of the 5-hydroxytryptophane challenge test combined with granisetron
Authors: Jacobs GE , Kamerling IMC , de Kam ML , DeRijk RH , van Pelt J. , Zitman FG , van Gerven JMA
Published: August 2008

A recently developed oral serotonergic challenge test consisting of 5-Hydroxytryptophane (5-HTP, 200 mg) combined with carbidopa (CBD, 100 mg + 50 mg) exhibited dose-related neuroendocrine responsiveness and predictable pharmacokinetics. However, its applicability is limited by nausea and vomiting. A randomized, double-blind, placebo-controlled, four-way crossover trial was performed in 12 healthy male volunteers. The 5-HTP/CBD-challenge was combined with two oral anti-emetics (granisetron, 2 mg or domperidone, 10 mg) to investigate its reliability when side-effects are suppressed. The neuroendocrine response (serum cortisol and prolactin), the side-effect profile [Visual Analogue Scale Nausea (VAS)] and vomiting subjects per treatment were the main outcome measures. Compared to 5-HTP/CBD/placebo, 5-HTP/CBD/ granisetron had no impact on cortisol [% change with 95% confidence interval: −7.1% (18.9; 6.5)] or prolactin levels [−9.6% (−25.1; 9.1)]; 5-HTP/CBD/domperidone increased cortisol [+13.0% (−4.2; 33.4)], and increased prolactin extensively [+336.8% (245.7; 451.9)]. Compared to placebo, VAS Nausea increased non-significantly with granisetron [+7.6 mm (−1.3; 16.5)], as opposed to domperidone [+16.2 mm (7.2; 25.2)] and 5-HTP/CBD/placebo [+14.7 mm (5.5; 23.8)]. No subjects vomited with granisetron, compared to two subjects treated with 5-HTP/CBD/placebo and five subjects with domperidone. Compared with 5-HTP/CBD/placebo, granisetron addition decreased Cmax of 5-HTP statistically significantly different (from 1483 to 1272 ng/ml) without influencing AUC0— ∞. Addition of granisetron to the combined 5-HTP/CBD challenge suppresses nausea and vomiting without influencing the neuroendocrine response or pharmacokinetics, enhancing its clinical applicability in future psychiatric research and drug development.
Examining the Relationship Between a Childhood History of Sexual Abuse and Later Dissociation, Breast-Feeding Practices, and Parenting Anxiety
Authors: Bowman Katherine Gail , Ryberg Jacalyn Wickline , Becker Heather
Published: August 2008

The purpose of this study is to compare Mexican American adolescent mothers with and without childhood sexual abuse (CSA) histories to examine the influence of CSA on dissociation, selection of infant feeding method, and intimate parenting anxiety. Participants are 78 English-speaking adolescents between 15 and 19 years of age and recruited from the southwestern United States. Nearly one third of the sample ( n = 24, 30.77%) reports CSA histories. There is no correlation between CSA history and intimate parenting anxiety, no difference between breast-feeding and formula-feeding mothers in CSA severity, and intimate parenting anxiety does not predict dissociation. These findings are inconsistent with previous research. Supportive resources may explain the inconsistency and play a role in adolescent mothers' responses to CSA. Further research is necessary to explore these possibilities.
`The Gods of My Father Terah': Abraham the Iconoclast and the Polemics with the Divine Body Traditions in the Apocalypse of Abraham
Authors: Orlov Andrei A.
Published: August 2008

The first eight chapters of the Apocalypse of Abraham recount the early years of the young hero of the faith who is depicted as a fighter against the idolatrous practices of his father Terah. The conceptual developments found in this section of the work, especially in the depictions of the idolatrous statues, seem to play an important role in the work's overall retraction of the anthropomorphic understanding of the deity. In the depictions of the idol Bar-Eshath (`the Son of Fire') and some other human-like figures, whose features are vividly reminiscent of the familiar attributes of the anthropomorphic portrayals of the deity in Ezekiel and some other biblical and pseudepigraphical accounts, one can detect subtle polemics with the divine body traditions. This article investigates these conceptual developments in the Apocalypse of Abraham and seeks to understand their place in the larger anti-corporeal ideology of the Slavonic pseudepigraphon.
Security: Collective Good or Commodity?
Authors: Krahmann Elke
Published: August 2008

The state monopoly on the legitimate use of violence in Europe and North America has been central to the development of security as a collective good. Not only has it institutionalized the state as the prime national and international security provider, it has helped to reduce the threat from other actors by either prohibiting or limiting their use of violence. The recent growth of the private security industry appears to undermine this view. Not only are private security firms proliferating at the national level; private military companies are also taking over an increasing range of military functions in both national defence and international interventions. This article seeks to provide an examination of the theoretical and practical implications of the shift from states to markets in the provision of security. Specifically, it discusses how the conceptualization of security as a commodity rather than a collective good affects the meaning and implementation of security in Western democracies.