bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreased plasma ghrelin contributes to anorexia following novelty stress
Authors: Saegusa Yayoi , Takeda Hiroshi , Muto Shuichi , Nakagawa Koji , Ohnishi Shunsuke , Sadakane Chiharu , Nahata Miwa , Hattori Tomohisa , Asaka Masahiro
Published: June 2011

We hypothesized that anorexia induced by novelty stress caused by exposure to a novel environment may be due to activation of corticotropin-releasing factor (CRF) and subsequently mediated by decreasing peripheral ghrelin concentration via serotonin (5-HT) and melanocortin-4 receptors (MC4R). Each mouse was transferred from group-housed cages to individual cages to establish the novelty stress. We observed the effect of changes in feeding behavior in a novel environment using the method of transferring group-housed mice to individual cages. We investigated the effect of an intracerebroventricular injection of antagonists/agonists of CRF1/2 receptors (CRF1/2Rs), 5-HT1B/2C receptors (5-HT1B/2CR), and MC4R to clarify the role of each receptor on the decrease in food intake. Plasma ghrelin levels were also measured. The novelty stress caused a reduction in food intake that was abolished by administering a CRF1R antagonist. Three hours after the novelty stress, appetite reduction was associated with reduced levels of neuropeptide Y/agouti-related peptide mRNA, increased levels of proopiomelanocortin mRNA in the hypothalamus, and a decrease in plasma ghrelin level. Administering a CRF1R antagonist, a 5-HT1B/2CR antagonist, an MC4R antagonist, exogenous ghrelin, and an enhancer of ghrelin secretion, rikkunshito, resolved the reduction in food intake 3 h after the novelty stress by enhancing circulating ghrelin concentrations. We showed that anorexia during a novelty stress is a process in which CRF1R is activated at the early stage of appetite loss and is subsequently activated by a 5-HT1B/2CR and MC4R stimulus, leading to decreased peripheral ghrelin concentrations.
Serum Calprotectin: An Antimicrobial Peptide as a New Marker For the Diagnosis of Sepsis in Very Low Birth Weight Newborns
Authors: Terrin Gianluca , Passariello Annalisa , Manguso Francesco , Salvia Gennaro , Rapacciuolo Luciano , Messina Francesco , Raimondi Francesco , Canani Roberto Berni
Published: June 2011

To determine the diagnostic utility of serum calprotectin, a mediator of innate immune response against infections, we performed a multicenter study involving newborns with a birth weight<1500 g and a postnatal age>72hours of life. The diagnostic accuracy of serum calprotectin was compared with that of the most commonly used markers of neonatal sepsis (white blood cell count, immature-to-total-neutrophil ratio, platelet count, and C-reactive protein). We found that the serum calprotectin concentration was significantly higher (P<.001) in 62 newborns with confirmed sepsis (3.1±1.0 μg/mL) than in either 29 noninfected subjects (1.1±0.3 μg/ml) or 110 healthy controls (0.91±0.58 μg/ml). The diagnostic accuracy of serum calprotectin was greater (sensitivity 89%, specificity 96%) than that of the traditional markers of sepsis. In conclusion, serum calprotectin is an accurate marker of sepsis in very low birth weight newborns.
Asymptotic Identity in Min-Plus Algebra: A Report on CPNS
Authors: Li Ming , Zhao Wei
Published: June 2011

Network calculus is a theory initiated primarily in computer communication networks, especially in the aspect of real-time communications, where min-plus algebra plays a role. Cyber-physical networking systems (CPNSs) are recently developing fast and models in data flows as well as systems in CPNS are, accordingly, greatly desired. Though min-plus algebra may be a promising tool to linearize any node in CPNS as can be seen from its applications to the Internet computing, there are tough problems remaining unsolved in this regard. The identity in min-plus algebra is one problem we shall address. We shall point out the confusions about the conventional identity in the min-plus algebra and present an analytical expression of the asymptotic identity that may not cause confusions.
HIF Induces Human Embryonic Stem Cell Markers in Cancer Cells
Authors: Mathieu Julie , Zhang Zhan , Zhou Wenyu , Wang Amy J. , Heddleston John M. , Pinna Claudia M.A. , Hubaud Alexis , Stadler Bradford , Choi Michael , Bar Merav , Tewari Muneesh , Liu Alvin , Vessella Robert , Rostomily Robert , Born Donald , Horwitz Marshall , Ware Carol , Blau C. Anthony , Cleary Michele A. , Rich Jeremy N. , Ruohola-Baker Hannele
Published: June 2011

Low oxygen levels have been shown to promote self-renewal in many stem cells. In tumors, hypoxia is associated with aggressive disease course and poor clinical outcomes. Furthermore, many aggressive tumors have been shown to display gene expression signatures characteristic of human embryonic stem cells (hESC). We now tested whether hypoxia might be responsible for the hESC signature observed in aggressive tumors. We show that hypoxia, through hypoxia-inducible factor (HIF), can induce an hESC-like transcriptional program, including the induced pluripotent stem cell (iPSC) inducers, OCT4, NANOG, SOX2, KLF4, cMYC, and microRNA-302 in 11 cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver, and breast tumors). Furthermore, nondegradable forms of HIFα, combined with the traditional iPSC inducers, are highly efficient in generating A549 iPSC-like colonies that have high tumorigenic capacity. To test potential correlation between iPSC inducers and HIF expression in primary tumors, we analyzed primary prostate tumors and found a significant correlation between NANOG-, OCT4-, and HIF1α-positive regions. Furthermore, NANOG and OCT4 expressions positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells, hypoxia was able to induce neurospheres and hESC markers. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathologic conditions. Cancer Res; 71(13); 4640–52. ©2011 AACR.
FoxM1: A Master Regulator of Tumor Metastasis
Authors: Raychaudhuri Pradip , Park Hyun Jung
Published: June 2011

The FoxM1 transcription factor gene is overexpressed in cancer. Its expression is stimulated by oncogenic signaling pathways and reactive oxygen species. It is also a target of regulation by the tumor suppressor genes. The transcriptional activity of FoxM1 depends upon activation by cyclin and cyclin-dependent kinases as well as Plk1. FoxM1 stimulates expression of several genes involved in the cell cycle progression. Moreover, it supports proliferation of tumor cells by stimulating expression of the antioxidant genes and reducing oxidative stress. A new study provides evidence that FoxM1, in the absence of its inhibitor, the tumor suppressor Arf, drives metastasis of hepatocellular carcinoma (HCC). It induces an epithelial–mesenchymal–like transition phenotype in HCC cells, increases cell migration, and induces premetastatic niche at the distal organ of metastasis. FoxM1 directly activates genes involved in multiple steps of metastasis. In this review, we discuss the evidence for a master regulatory role of FoxM1 in tumor metastasis. Cancer Res; 71(13); 4329–33. ©2011 AACR.
Treatment-Induced Oxidative Stress and Cellular Antioxidant Capacity Determine Response to Bortezomib in Mantle Cell Lymphoma
Authors: Weniger Marc A. , Rizzatti Edgar G. , Pérez-Galán Patricia , Liu Delong , Wang Qiuyan , Munson Peter J. , Raghavachari Nalini , White Therese , Tweito Megan M. , Dunleavy Kieron , Ye Yihong , Wilson Wyndham H. , Wiestner Adrian
Published: June 2011

Purpose: Proteasome inhibition disrupts protein homeostasis and induces apoptosis. Up to 50% of patients with relapsed mantle cell lymphoma (MCL) respond to bortezomib. We used gene expression profiling to investigate the connection between proteasome inhibition, cellular response, and clinical efficacy.

Experimental Design: We assessed transcriptional changes in primary tumor cells from five patients during treatment with bortezomib in vivo, and in 10 MCL cell lines exposed to bortezomib in vitro, on Affymetrix microarrays. Key findings were confirmed by western blotting.

Results: MCL cell lines exposed to bortezomib in vitro showed upregulation of endoplasmic reticulum and oxidative stress response pathways. Gene expression changes were strongest in bortezomib-sensitive cells and these cells were also more sensitive to oxidative stress induced by H2O2. Purified tumor cells obtained at several timepoints during bortezomib treatment in 5 previously untreated patients with leukemic MCL showed strong activation of the antioxidant response controlled by NRF2. Unexpectedly, activation of this homeostatic program was significantly stronger in tumors with the best clinical response. Consistent with its proapoptotic function, we found upregulation of NOXA in circulating tumor cells of responding patients. In resistant cells, gene expression changes in response to bortezomib were limited and upregulation of NOXA was absent. Interestingly, at baseline, bortezomib-resistant cells displayed a relatively higher expression of the NRF2 gene-expression signature than sensitive cells (P < 0.001).

Conclusion: Bortezomib triggers an oxidative stress response in vitro and in vivo. High cellular antioxidant capacity contributes to bortezomib resistance. Clin Cancer Res; 17(15); 5101–12. ©2011 AACR.
Cancer Patients Treated with Sunitinib or Sorafenib Have Sufficient Antibody and Cellular Immune Responses to Warrant Influenza Vaccination
Authors: Mulder Sasja F. , Jacobs Joannes F.M. , Olde Nordkamp Michel A.M. , Galama Joep M.D. , Desar Ingrid M.E. , Torensma Ruurd , Teerenstra Steven , Mulders Peter F.A. , Vissers Kris C.P. , Punt Cornelis J.A. , de Vries I. Jolanda M. , van Herpen Carla M.L.
Published: June 2011

Purpose: The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib.

Patients and Methods: Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines.

Results: Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls.

Conclusion: We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib. Clin Cancer Res; 17(13); 4541–9. ©2011 AACR.
Liposomal Delivery of MicroRNA-7–Expressing Plasmid Overcomes Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistance in Lung Cancer Cells
Authors: Rai Kammei , Takigawa Nagio , Ito Sachio , Kashihara Hiromi , Ichihara Eiki , Yasuda Tatsuji , Shimizu Kenji , Tanimoto Mitsune , Kiura Katsuyuki
Published: June 2011

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been strikingly effective in lung cancers harboring activating EGFR mutations. Unfortunately, the cancer cells eventually acquire resistance to EGFR-TKI. Approximately 50% of the acquired resistance involves a secondary T790M mutation. To overcome the resistance, we focused on EGFR suppression using microRNA-7 (miR-7), targeting multiple sites in the 3′-untranslated region of EGFR mRNA. Two EGFR-TKI–sensitive cell lines (PC-9 and H3255) and two EGFR-TKI–resistant cell lines harboring T790M (RPC-9 and H1975) were used. We constructed miR-7-2 containing miR-7–expressing plasmid. After transfection of the miR-7–expressing plasmid, using cationic liposomes, a quantitative PCR and dual luciferase assay were conducted to examine the efficacy. The antiproliferative effect was evaluated using a cell count assay and xenograft model. Protein expression was examined by Western blotting. The miR-7 expression level of the transfectants was approximately 30-fold higher, and the luciferase activity was ablated by 92%. miR-7 significantly inhibited cell growth not only in PC-9 and H3255 but also in RPC-9 and H1975. Expression of insulin receptor substrate-1 (IRS-1), RAF-1, and EGFR was suppressed in the four cell lines. Injection of the miR-7–expressing plasmid revealed marked tumor regression in a mouse xenograft model using RPC-9 and H1975. EGFR, RAF-1, and IRS-1 were suppressed in the residual tumors. These findings indicate promising therapeutic applications of miR-7–expressing plasmids against EGFR oncogene–addicted lung cancers including T790M resistance by liposomal delivery. Mol Cancer Ther; 10(9); 1720–7. ©2011 AACR.
Lack of Transient Receptor Potential Vanilloid-1 Enhances Th2-Biased Immune Response of the Airways in Mice Receiving Intranasal, but Not Intraperitoneal, Sensitization
Authors: Mori Tetsuya , Saito Katsuyo , Ohki Yasushi , Arakawa Hirokazu , Tominaga Makoto , Tokuyama Kenichi
Published: June 2011

Background: Transient receptor potential vanilloid-1 (TRPV1) may modulate allergic airway inflammation because it is expressed not only on the nerve endings but also on several cells of the immune system. We wanted to know the characteristics of airway and systemic responses against sensitization and challenge with allergens in TRPV1 receptor gene knockout mice (TRPV1–/–). Methods: TRPV1–/– and their wild-type counterparts (TRPV1+/+) were sensitized with either house dust mite (HDM) or ovalbumin (OVA) via intranasal (i.n.) or intraperitoneal (i.p.) route before the final i.n. challenge with the corresponding allergen. One day after the final challenge, serum IgE levels, cytokine levels in the bronchoalveolar lavage fluid (BALF), and the number of BALF cells were examined after measuring bronchial hyperresponsiveness against methacholine. Results: Compared to TRPV1+/+, TRPV1–/– showed enhanced Th2-biased response after i.n. HDM or OVA sensitization, including increased levels of serum IgE, interleukin 4 (IL-4) and eosinophils in the BALF. By contrast, when sensitized via i.p. route, the response against OVA or HDM was almost similar between TRPV1+/+ and TRPV1–/–. Conclusion: TRPV1 receptor may downregulate Th2-biased immune response when sensitized via airways, although this was not the case when sensitized systemically.
Hypersensitivity Reactions to Docetaxel: Retrospective Evaluation and Development of a Desensitization Protocol
Authors: Syrigou Ekaterini , Dannos Ioannis , Kotteas Elias , Makrilia Nektaria , Tourkantonis Ioannis , Dilana Kalliopi , Gkiozos Ioannis , Saif Muhammad Wasif , Syrigos Kostas N.
Published: June 2011

Background: Docetaxel (DT) is an extensively used taxane, frequently associated with hypersensitivity reactions. The aim of this study was to record the epidemiological and clinical features of hypersensitivity to DT in non-small cell lung cancer patients in order to obtain useful information concerning the management of these patients. We also developed a desensitization protocol and evaluated its clinical application. Methods: We retrospectively reviewed records of 620 non-small cell lung cancer patients treated with DT-containing regimens in the adjuvant, first-, second- or next-line setting. Data from 102 patients who had exhibited hypersensitivity reactions were analyzed according to the Common Toxicity Criteria for Adverse Events version 3.0. Five patients were chosen for the desensitization protocol. We applied the standard protocol for parenteral desensitization to β-lactam antibiotics, and DT treatment was carried out with a series of 10-fold dilutions in sufficient volume to administer the total dose. Results: One hundred and two patients (16.5%) were recorded as having hypersensitivity to DT. Reactions were observed after approximately 2.5 ± 1.0 cycles. Only 14 patients (14/620, 2%) developed grade 3–4 hypersensitivity. Reactions were more likely in patients during second- or third-line chemotherapy, but no other correlation (age, gender, atopic status) was observed. Five patients completed a parenteral desensitization protocol and continued their treatment uneventfully. Conclusions: Hypersensitivity reactions to DT respond quickly to discontinuation along with appropriate supportive care. Premedication and increased infusion time may allow readministration. The desensitization protocol that we developed provides a reliable alternative to permanent discontinuation of DT.
De novo Partial Trisomy 18p and Partial Monosomy 18q in a Patient with Anorectal Malformation
Authors: Bartels E. , Draaken M. , Kazmierczak B. , Spranger S. , Schramm C. , Baudisch F. , Nöthen M.M. , Schmiedeke E. , Ludwig M. , Reutter H.
Published: June 2011

Anorectal malformations (ARM) encompass a broad clinical spectrum which ranges from mild anal stenosis to severe anorectal anomalies such as complex cloacal malformations. The overall incidence of ARM is around 1 in every 2,500 live births. Although causative genes for a few syndromic forms have been identified, the molecular genetic background of most ARM remains unknown. The present report describes a patient with a de novo 13.2-Mb deletion of chromosome 18q22.3–qter and a 2.2-Mb de novo duplication of chromosomal region 18pter–p11.32 located at the telomeric end of chromosome 18q. The patient presented with ARM and the typical features of 18q– syndrome (De-Grouchy syndrome). The combination of a partial duplication of the short arm and a partial deletion of the long arm of chromosome 18 has been described in 16 previous cases. However, this is the first report of an association between this complex chromosomal rearrangement and ARM.
Polymorphism in a Human Chromosome-Specific Interstitial Telomere-Like Sequence at 22q11.2
Authors: Samassekou O. , Yan J.
Published: June 2011

Interstitial telomeric sequences (ITSs) are common in human. We previously reported the presence of an ITS at 22q11.2 which is in the vicinity of the genomically unstable region involved in 22q11 rearrangements. Recently, we studied the molecular status of the ITS 22q11.2 in the normal population. The amplification of an ITS at 22q11.2 showed different patterns ranging from 1–4 kb, confirming the highly polymorphic nature of this sequence. The linkage analysis of the ITS at 22q11.2 in members of 10 different families demonstrated a strong relation between offspring and parents. In contrast, the study of a DiGeorge case and his 2 parents revealed the presence of a novel allele probably inherited from the father. These results open an avenue for the use of this sequence as an allelic marker, and its implication in 22q11.2-related pathogenesis.
Structural Heterozygosity, Duplication of Telomeric (TTTAGGG)n Clusters and B Chromosome Architecture in Tradescantia virginiana L.
Authors: Golczyk H.
Published: June 2011

Fluorescent in situ hybridization, C-banding/DAPI, and CMA3-fluorescence were performed to reveal the cytomolecular constitution of the standard (A) and supernumerary (B) chromosomes of an autotetraploid Tradescantia virginiana L. The analyses show that translocations and/or inversions have occurred during the evolution of the T. virginiana karyotype, generating a significant level of structural heterozygosity. Regarding the structural level, the present paper confirms the occurrence of small subterminal duplications and/or inversions in T. virginiana already suggested by previous authors. Interestingly, many of the distal chromosome segments in T. virginiana possess duplicated subterminal telomere clusters, heterochromatin, 5S and 45S rDNAs orderly intermixed and share this complex cytomolecular architecture with the common type of a B chromosome. Based on the obtained results, it is proposed that in T. virginiana the B chromosome may have arisen via excision from the distal region of an A chromosome. The nascent B could have retained much of the ancestral sequence arrangement, including duplicated telomeric cluster(s), heterochromatin and rDNA, but developed a new centromere/kinetochore to successfully propagate through the cell cycle.
Angiotensin II Activation of mTOR Results in Tubulointerstitial Fibrosis through Loss of N-Cadherin
Authors: Whaley-Connell Adam , Habibi Javad , Panfili Zachary , Hayden Melvin R. , Bagree Sarika , Nistala Ravi , Hyder Safwan , Krueger Bennett , DeMarco Vincent , Pulakat Lakshmi , Ferrario Carlos M. , Parrish Alan , Sowers James R.
Published: June 2011

Background/Aims: Angiotensin (Ang) II contributes to tubulointerstitial fibrosis. Recent data highlight mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling in tubulointerstitial fibrosis; however, the mechanisms remain unclear. Thereby, we investigated the role of Ang II on mTOR/S6K1-dependent proximal tubule (PT) injury, remodeling, and fibrosis. Methods: We utilized young transgenic Ren2 rats (R2-T) and Sprague-Dawley rats (SD-T) treated with the Ang type 1 receptor (AT1R) blocker telmisartan (2 mg · kg–1 · day–1) or vehicle (R2-C; SD-C) for 3 weeks to examine PT structure and function. Results: Ren2 rats displayed increased systolic blood pressure, proteinuria and increased PT oxidant stress and remodeling. There were parallel increases in kidney injury molecule-1 and reductions in neprilysin and megalin with associated ultrastructural findings of decreased clathrin-coated pits, endosomes, and vacuoles. Ren2 rats displayed increased Serine2448 phosphorylation of mTOR and downstream S6K1, in concert with ultrastructural basement membrane thickening, tubulointerstitial fibrosis and loss of the adhesion molecule N-cadherin. Telmisartan treatment attenuated proteinuria as well as the biochemical and tubulointerstitial structural abnormalities seen in the Ren2 rats. Conclusions: Our observations suggest that Ang II activation of the AT1R contributes to PT brush border injury and remodeling, in part, due to enhanced mTOR/S6K1 signaling which promotes tubulointerstitial fibrosis through loss of N-cadherin.
Involvement of microparticles in diabetic vascular complications
Authors: Tsimerman Gala , Roguin Ariel , Bachar Anat , Melamed Eyal , Brenner Benjamin , Aharon Anat
Published: June 2011

Type 2 diabetes mellitus (T2DM) is associated with increased coagulability and vascular complications. Circulating microparticles (MPs) are involved in thrombosis, inflammation, and angiogenesis. However, the role of MPs in T2DM vascular complications is unclear. We characterised the cell origin and pro-coagulant profiles of MPs obtained from 41 healthy controls and 123 T2DM patients with coronary artery disease, retinopathy and foot ulcers. The effects of MPs on endothelial cell coagulability and tube formation were evaluated. Patients with severe diabetic foot ulcers expressed the highest levels of MPs originated from platelet and endothelial cells and negatively-charged phospholipidbearing MPs. MP coagulability, calculated from MP tissue factor (TF) and TF pathway inhibitor (TFPI) ratio, was low in healthy controls and in diabetic retinopathy patients (<0.7) but high in patients with coronary artery disease and foot ulcers (>1.8, p≥0.002). MPs of all T2DM patients induced a more than two-fold increase in endothelial cell TF (antigen and gene expression) but did not affect TFPI levels. Tube networks were longest and most stable in endothelial cells that were incubated with MPs of healthy controls, whereas no tube formation occurred in MPs of diabetic patients with coronary artery disease. MPs of diabetic retinopathy and diabetic foot ulcer patients induced branched tube networks that were unstable and collapsed over time. This study demonstrates that MP characteristics are related to the specific type of vascular complications and may serve as a bio-marker for the procoagulant state and vascular pathology in patients with T2DM.
The effect of decitabine on megakaryocyte maturation and platelet release
Authors: Wang Jianhui , Yi Zanhua , Wang Shiyang , Li Zongdong
Published: June 2011

Thrombocytopenia is a common feature of myelodysplastic syndromes (MDS). 5-aza-2’-deoxycytidine (decitabine) has been used to treat MDS with an approximately 20% response rate in thrombocytopenia. However, the mechanism of how decitabine increases platelet count is not clear. In this study, we investigated the effect of decitabine on megakaryocyte maturation and platelet release in the mouse. The effect of decitabine on megakaryocyte maturation was studied in an in vitro megakaryocyte differentiation model utilising mouse bone marrow cells and mouse megakaryoblastic cell line L8057. Decitabine (2.5 μM) is able to induce L8057 cells to differentiate into a megakaryocyte-like polyploidy cells with positive markers of acetylcholinesterase and αIIb integrin (CD41). Higher expression of αIIb integrin was also found in primary mouse bone marrow cells and human cord blood CD34+ cells cultured with both thrombopoietin and decitabine as compared to thrombopoietin alone. In addition, we noted a 30% platelet count increase in Balb/c mice 12 hours after the injection of decitabine at a clinically relevant dose (15 mg/m2), suggesting a rapid platelet release from the spleen or bone marrow. Our data suggest that decitabine increases platelet counts by enhancing platelet release and megakaryocyte maturation.
The inhibition effect of anti-GPIIIa49–66 antibody on megakaryocyte differentiation
Authors: Nardi Michael , Pan Ruimin , Wang Jianhui , Li Zongdong
Published: June 2011

We previously reported that patients with early-onset HIV-1 ITP developed a unique anti-platelet integrin GPIIIa antibody against the GPIIIa49–66 epitope. Anti-GPIIIa49–66 antibody-induced platelet fragmentation requires sequential activation of the platelet 12-lipoxygenase (12-LO) and NADPH oxidase to release reactive oxygen species (ROS). 12-LO is upstream of the NADPH oxidase pathway and 12(S)- HETE, the product of 12-LO, induces the same oxidative platelet fragmentation as anti-GPIIIa49–66. Since the megakaryocyte (MK) is the progenitor cell for platelets, we have investigated the effect of anti- GPIIIa49–66 on MK differentiation and, in particular, the potential role of anti-GPIIIa49–66 induced ROS in this process. We first show that polyclonal anti-GPIIIa49–66 antibody isolated from HIV-1 ITP patients inhibits MK proliferation 2.5-fold in in vitro culture of human cord blood CD34+ cells driven by thrombopoietin (TPO). We also observe a three-fold decrease in the number of MK colony-forming units in the presence of a human monoclonal anti-GPIIIa49–66 antibody. However, we could not detect ROS release in DCFH-loaded mouse megakaryoblastic cells L8057 treated with anti-GPIIIa49–66 antibody. In addition, 12(S)-HETE does not inhibit the in vitro differentiation of L8057 cells induced by TPO. In fact, we found a dose dependent increase in the percentage of CD41 positive cells (from 17.1% to 48.7%) in in vitro culture of L8057 cells treated with various concentrations of H2O2 (from 5 to 20 μM). We therefore conclude that the anti-GPIIIa49–66 antibody inhibits MK differentiation through β3 integrin signalling independent of ROS release.
Potent Long-Term Cardioprotective Effects of Single Low-Dose Insulin-Like Growth Factor-1 Treatment Postmyocardial Infarction
Authors: O'Sullivan John F. , Leblond Anne-Laure , Kelly Geraldine , Kumar Arun H.S. , Metharom Pat , Büneker Chirlei K. , Alizadeh-Vikali Niki , Hristova Ivalina , Hynes Brian G. , O'Connor Rosemary , Caplice Noel M.
Published: June 2011

Background—

Insulin-like growth factor-1 (IGF-1) is recognized as an important regulator of cardiac structure and cardiomyocyte homeostasis. The prosurvival and antiapoptotic effects of IGF-1 have been investigated in vitro and in rodent models of myocardial infarction (MI). However, the clinical application of IGF-1 has been hampered by dose-dependent side effects both acutely and during chronic administration. We hypothesized that single, low-dose IGF-1 (LD-IGF-1) administered locally and early in the reperfusion phase after acute MI in a large animal model would avoid significant side effects but would have prosurvival effects that would manifest in long-term structural and functional improvement after MI treatment.

Methods and Results—

Forty-four female Landrace pigs underwent intracoronary administration of LD-IGF-1 or saline 2 hours into the reperfusion phase of acute left anterior descending artery occlusion MI. In the area of infarction, IGF-1 receptor and signaling responses were activated at 30 minutes and cardiomyocyte cell death attenuated at 24 hours after LD-IGF-1 but not saline treatment. Hemodynamic and structural studies using pressure-volume loop, CT, and triphenyltetrazolium chloride analysis 2 months post-MI confirmed a marked reduction in infarct size, attenuation of wall thinning, and augmentation of wall motion in the LD-IGF-1-treated but not in the saline-treated animals. These regional structural benefits were associated with global reductions in left ventricular volumes and significant improvement in left ventricular systolic and diastolic function.

Conclusions—

One-time LD-IGF-1 effects potent acute myocardial salvage in a preclinical model of left anterior descending artery occlusive MI, extending to long-term benefits in MI size, wall structure, and function and underscoring its potential as an adjunctive therapeutic agent.
Sirolimus-Eluting Stent Implantation for Ostial Left Anterior Descending Coronary Artery Lesions
Authors: Kishi Koichi , Kimura Takeshi , Morimoto Takeshi , Namura Masanobu , Muramatsu Toshiya , Nishikawa Hideo , Hiasa Yoshikazu , Isshiki Takaaki , Nobuyoshi Masakiyo , Mitsudo Kazuaki ,   for the j-Cypher Registry Investigators
Published: June 2011

Background—

Ostial left anterior descending coronary artery (LAD) lesion has been regarded as a lesion subset unsuitable for coronary stenting. Long-term outcomes of sirolimus-eluting stent (SES) implantation for ostial LAD lesions have not been adequately evaluated.

Methods and Results—

Among 12 824 patients enrolled in the j-Cypher Registry, 3-year outcomes were compared between 481 patients with SES-treated ostial LAD lesions and 5369 patients with SES-treated nonostial proximal LAD lesions. Patients with ostial LAD lesions had similar incidences of target lesion revascularization (TLR) as those with nonostial proximal LAD lesions (9.4% versus 9.7%;
P
=0.98; adjusted hazard ratio [HR], 0.99; 95% CI, 0.7 to 1.36;
P
=0.94) and death/myocardial infarction (MI) (10.7% versus 11.4%;
P
=0.82; adjusted HR, 1.05; 95% CI, 0.76 to 1.4;
P
=0.77). Among the patients with ostial LAD lesions, those undergoing both main and side branch stenting (n=62) compared to main branch stenting alone (n=419) had a higher risk for TLR (adjusted HR, 4.65; 95% CI, 2.32 to 9.25;
P
<0.0001) but similar risk for death/MI (adjusted HR, 1.15; 95% CI, 0.49 to 2.41;
P
=0.73). In patients with main branch stenting alone, outcomes after crossover stenting across the circumflex coronary artery (n=225) were not different from those after ostial stenting (n=194) for TLR (adjusted HR, 0.77; 95% CI, 0.33 to 1.82;
P
=0.55) and for death/MI (adjusted HR, 1.54; 95% CI, 0.78 to 3.2;
P
=0.22).

Conclusions—

In terms of both safety and efficacy, 3-year outcomes of percutaneous coronary intervention using SES for ostial LAD lesions were comparable to those for nonostial proximal LAD lesions. Crossover stenting with a 1-stent approach might be a reasonable option in treating ostial LAD lesions.
Long-Term Follow-Up of Early Versus Delayed Invasive Approach After Fibrinolysis in Acute Myocardial Infarction
Authors: Clever Yvonne P. , Cremers Bodo , Link Andreas , Böhm Michael , Scheller Bruno
Published: June 2011

Background—

Optimal reperfusion strategy in ST-elevation myocardial infarction is controversial. Failure of fibrinolytic therapy is related to limited efficacy, high reocclusion rates, reinfarction, and systemic bleeding complications. Data on the impact of percutaneous coronary intervention (PCI) after fibrinolysis are conflicting. The Southwest German Interventional Study in Acute Myocardial Infarction (SIAM III) evaluated the effects of transfer for early PCI in acute ST-elevation–myocardial infarction compared with a delayed PCI strategy.

Methods and Results—

SIAM III was a multicenter, randomized, prospective, controlled trial in patients with ST-elevation–myocardial infarction receiving fibrinolysis <12 hours after onset of symptoms. All patients received reteplase, aspirin in combination with ticlopidine, and heparin. Patients of the early PCI group were transferred within 6 hours after fibrinolysis for PCI. The delayed PCI group received elective PCI 2 weeks after fibrinolysis. In total, 197 patients were included; 163 were treated by PCI. The primary end point was the composite of death, reinfarction, target lesion revascularization, and ischemic events. During a mean follow-up time of 7.9±3.4 years (maximum, 11.2 years), early PCI was associated with a significant reduction of the primary end point (hazard ratio, 0.61 [95% confidence interval, 0.42 to 0.88];
P
=0.008). Long-term survival was higher in the early PCI group (
P
=0.057). Ischemic events were significantly reduced after early PCI (
P
=0.003).

Conclusions—

Early PCI after fibrinolysis improves long-term event-free survival compared with a delayed PCI treatment strategy.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01124890.
The Risk of Incident Coronary Heart Disease Among Veterans With and Without HIV and Hepatitis C
Authors: Freiberg Matthew S. , Chang Chung-Chou H. , Skanderson Melissa , McGinnis Kathleen , Kuller Lewis H. , Kraemer Kevin L. , Rimland David , Goetz Matthew B. , Butt Adeel A. , Rodriguez Barradas Maria C. , Gibert Cynthia , Leaf David , Brown Sheldon T. , Samet Jeffrey , Kazis Lewis , Bryant Kendall , Justice Amy C. ,   for the Veterans Aging Cohort Study
Published: June 2011

Background—

Whether hepatitis C virus (HCV) confers additional coronary heart disease (CHD) risk among human immunodeficiency virus (HIV) infected individuals is unclear. Without appropriate adjustment for antiretroviral therapy, CD4 count, and HIV-1 RNA and substantially different mortality rates among those with and without HIV and HCV infection, the association between HIV, HCV, and CHD may be obscured.

Methods and Results—

We analyzed data on 8579 participants (28% HIV+, 9% HIV+HCV+) from the Veterans Aging Cohort Study Virtual Cohort who participated in the 1999 Large Health Study of Veteran Enrollees. We analyzed data collected on HIV and HCV status, risk factors for and the incidence of CHD, and mortality from January 2000 to July 2007. We compared models to assess CHD risk when death was treated as a censoring event and as a competing risk. During the median 7.3 years of follow-up, there were 194 CHD events and 1186 deaths. Compared with HIV−HCV− Veterans, HIV+HCV+ Veterans had a significantly higher risk of CHD regardless of whether death was adjusted for as a censoring event (adjusted hazard ratio, 2.03; 95% confidence interval, 1.28 to 3.21) or a competing risk (adjusted HR, 2.45; 95% confidence interval, 1.83 to 3.27 respectively). Compared with HIV+HCV− Veterans, HIV+HCV+ Veterans also had a significantly higher adjusted risk of CHD regardless of whether death was treated as a censored event (adjusted hazard ratio, 1.93; 95% confidence interval, 1.02 to 3.62) or a competing risk (adjusted hazard ratio, 1.46; 95% confidence interval, 1.03 to 2.07).

Conclusions—

HIV+HCV+ Veterans have an increased risk of CHD compared with HIV+HCV− and HIV−HCV− Veterans.
Upstream Use of Small-Molecule Glycoprotein IIb/IIIa Inhibitors in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes
Authors: Tricoci Pierluigi , Newby L. Kristin , Hasselblad Vic , Kong David F. , Giugliano Robert P. , White Harvey D. , Théroux Pierre , Stone Gregg W. , Moliterno David J. , Van de Werf Frans , Armstrong Paul W. , Prabhakaran Dorairaj , Rasoul Saman , Bolognese Leonardo , Durand Eric , Braunwald Eugene , Califf Robert M. , Harrington Robert A.
Published: June 2011

Background—

The use of upstream small-molecule glycoprotein (GP) IIb/IIIa inhibitors in non–ST-segment elevation acute coronary syndromes (NSTE ACS) has been studied in multiple randomized clinical trials. We systematically reviewed the effect of upstream GP IIb/IIIa inhibitor use in NSTE ACS as reported in published clinical trials.

Methods and Results—

Randomized clinical trials of upstream small-molecule GP IIb/IIIa inhibitors in NSTE ACS were identified through a PubMed and EMBASE search and were included if they contained 30-day outcome data. Odds ratios were generated from the published data and pooled by means of random effects modeling. The primary outcome measures were 30-day death and 30-day death or myocardial infarction. Primary safety measures were major bleeding and transfusion during the index hospitalization. Twelve clinical trials were included, evaluating tirofiban, eptifibatide, and lamifiban. Of these, 7 evaluated upstream GP IIb/IIIa inhibitors versus placebo (n=24 031) and 5 evaluated a strategy of upstream GP IIb/IIIa inhibitors versus upstream placebo with later provisional use at the time of percutaneous coronary intervention (n=19 643). Overall, upstream GP IIb/IIIa inhibitor use was associated with an 11% reduction in 30-day death/myocardial infarction (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.83 to 0.95) but no significant mortality effect (OR, 0.93; 95% CI, 0.83 to 1.05). The risk of major bleeding was 23% higher in patients treated with upstream GP IIb/IIIa inhibitors (OR, 1.23; 95% CI, 1.02 to 1.48). Results were similar when only trials comparing upstream GP IIb/IIIa inhibitors versus placebo were considered: 30-day death/myocardial infarction (OR, 0.88; 95% CI, 0.81 to 0.95); 30-day death (OR, 0.89; 95% CI, 0.76 to 1.03); and major bleeding (OR, 1.17; 95% CI, 0.88 to 1.54). Upstream versus selective use at percutaneous coronary intervention trended toward lower 30-day death/myocardial infarction (OR, 0.91; 95% CI, 0.82 to 1.01) but had no effect on mortality (OR, 1.00; 95% CI, 0.81 to 1.23) and increased major bleeding risk by 34% (OR, 1.34; 95% CI, 1.10 to 1.63).

Conclusions—

In NSTE ACS, treatment with upstream small-molecule GP IIb/IIIa inhibitors provides a significant but modest ischemic benefit when compared with initial placebo. Compared with delayed, selective use at percutaneous coronary intervention, early upstream use is associated with a trend toward fewer ischemic events. However, these modest benefits are associated with an increased risk of bleeding.
The Business Case for Quality Improvement
Authors: Rose Adam J. , Berlowitz Dan R. , Ash Arlene S. , Ozonoff Al , Hylek Elaine M. , Goldhaber-Fiebert Jeremy D.
Published: June 2011

Background—

The potential to save money within a short time frame provides a more compelling “business case” for quality improvement than merely demonstrating cost-effectiveness. Our objective was to demonstrate the potential for cost savings from improved control in patients anticoagulated for atrial fibrillation.

Methods and Results—

Our population consisted of 67 077 Veterans Health Administration patients anticoagulated for atrial fibrillation between October 1, 2006, and September 30, 2008. We simulated the number of adverse events and their associated costs and utilities, both before and after various degrees of improvement in percent time in therapeutic range (TTR). The simulation had a 2-year time horizon, and costs were calculated from the perspective of the payer. In the base-case analysis, improving TTR by 5% prevented 1114 adverse events, including 662 deaths; it gained 863 quality-adjusted life-years and saved $15.9 million compared with the status quo, not accounting for the cost of the quality improvement program. Improving TTR by 10% prevented 2087 events, gained 1606 quality-adjusted life-years, and saved $29.7 million. In sensitivity analyses, costs were most sensitive to the estimated risk of stroke and the expected stroke reduction from improved TTR. Utilities were most sensitive to the estimated risk of death and the expected mortality benefit from improved TTR.

Conclusions—

A quality improvement program to improve anticoagulation control probably would be cost-saving for the payer, even if it were only modestly effective in improving control and even without considering the value of improved health. This study demonstrates how to make a business case for a quality improvement initiative.
Influence of Humidified Aerosol on Lidar Depolarization Measurements below Ice-Precipitating Arctic Stratus
Authors: van Diedenhoven Bastiaan , Fridlind Ann M. , Ackerman Andrew S.
Published: June 2011

Lidar measurements obtained during the Surface Heat Budget of the Arctic Ocean (SHEBA) experiment under a mixed-phase stratus cloud that was lightly precipitating ice show a range of surprisingly low depolarization ratios (4%–23%), despite an absence of cloud droplets there. These depolarization ratios are much lower than the range of theoretical values obtained for various ice habits. The depolarization ratios correlate well with radar reflectivity, suggesting that the variation in depolarization ratios results from variations in ice water content, rather than variation in ice habits or orientation. By calculating lidar depolarization based on (i) large-eddy simulations and (ii) in situ ice size distribution measurements, it is shown that the presence of humidified aerosol particles in addition to the ice precipitation can explain the distribution and vertical profile of the observed depolarization ratios, although uncertainties related to the aerosol size distributions are substantial. These calculations show that humidified aerosol must be taken into account when interpreting lidar depolarization measurements for cloud and precipitation phase discrimination or ice habit classification, at least under conditions similar to those observed during SHEBA.
Introduction: Professions and organizations - a conceptual framework
Authors: Muzio Daniel , Kirkpatrick Ian
Published: June 2011

This collection seeks to reconnect two separate streams of work on professional organizations and professional occupations. In particular the articles collected here identify two key themes: (1) the challenges and opportunities that professional organizations pose for established and emerging professionalization projects and (2) the extent to which professional organizations create, institutionalize and manipulate new forms of professionalism and models of professionalization. To this effect, this collection brings together a number of articles from a broad range of disciplines (sociology, management, healthcare, accountancy, law and geography), theoretical backgrounds and national contexts which explore the complex connections between professional occupations and organizations.
A new professionalism? Challenges and opportunities
Authors: Evetts Julia
Published: June 2011

Sociologists interested in professional work and occupations have differentiated professionalism as a distinctive and special way of controlling and organizing work and workers, with real advantages for both practitioners and clients. In this interpretation the analysis of professionalism is as an ‘occupational value’. But professionalism is changing and being changed as professionals now increasingly work in large-scale organizational workplaces and sometimes in international firms. This article explains professionalism as an occupational value and indicates both the changes to and continuities in professionalism in these organizational contexts. Then some of the possible consequences of the redefinition of professionalism are examined for practitioner-workers and their clients in public sector service work such as health, welfare and education. These consequences include changes in the work itself, in practitioner—employer and practitioner—client relations, and in the control of work priorities and processes. The final section considers if there might also be some advantages in the combination of professional and organizational logics for controlling work and workers and whether there are opportunities associated with these changes which might improve both the conduct and practice of professional service work, while being of benefit to practitioners and clients.
Making sense of career in a Big Four accounting firm
Authors: Mueller Frank , Carter Chris , Ross-Smith Anne
Published: June 2011

There is little existing research on how managers within the ‘Big Four’ professional services firms (PSFs) respond to the increasing normative pressures and performative cultures that characterize contemporary PSFs. It is primarily managers within PSFs that enact the new managerial roles, systems and ethos that differentiate ‘managed professional businesses’ (MPBs) from the P2 archetype. It is managers who in their own estimation need to ensure that both organization and employees perform to the required standard. This article reports from an empirical study into one of the Big Four accounting firms. The focus is on how a specific group of employees, namely female managers, make sense of career and performance in their particular organization. The respondents’ career is being shaped by their real and perceived willingness to be ‘bothered to be playing the game’ as well as providing a good client service and participating in the ongoing rationalization of professional practices. Thus, the self is divided: on the one hand, ambitious, committed and loyal to the firm and to the notion of performing. On the other hand, there is also distancing and disenchantment with the existing practices and reluctant acknowledgement that the reality is characterized by a culture of visibility and exposure; the need to network, play politics and be playing-the-game, none of which are gender-neutral.
Mary—The Jewish Mother
Authors: Kessler Edward
Published: June 2011

Christians have re-awoken to the Jewishness of Jesus and rediscovered a respect for Judaism. Is it not time to reconsider Mary, in Jewish terms? Mary was an observant Jewish woman and she even carried on worshipping at the Temple in Jerusalem after the Christ Event. Although on the cusp of the divide between Judaism and Christianity, within a few centuries the Church was playing down her Jewishness and soon applied anti-Jewish teaching. By the early Middle Ages, Jews had responded with their own polemic, notably against the belief that Christ was born of a virgin. The Jewish rejection of the Virgin Birth resulted in a view of Jews as particular enemies of Mary, an understanding which was explored in medieval art and miracle tales. Today Catholics and Jews can redeem this antiquated understanding of Mary by portraying her positively—as a first-century Jewish mother.
The Resurrection and Bereavement Experiences
Authors: Gerald O’Collins SJ
Published: June 2011

This article presents and evaluates an analogy between the appearances of the risen Christ to his disciples and the experiences that many widows and widowers have of their deceased spouses. After his pioneering work on such bereavement experiences (published in 1971), Dr Dewi Rees produced further publications in this area, and in Pointers to Eternity (2010) he has proposed the case for the analogy in detail. This article argues that there are too many dissimilarities for the analogy to be acknowledged as close and illuminating, but recognizes how the work of Rees and his successors can serve to confirm Easter faith and hope for some people, especially the bereaved who experience their dead spouses.