bluuebunny/crossref_metadata_2025 huggingface dataset:
Effective Immunoconjugate Therapy in Cancer Models Targeting a Serine Protease of Tumor Fibroblasts
Authors: Ostermann Elinborg , Garin-Chesa Pilar , Heider Karl Heinz , Kalat Milena , Lamche Herbert , Puri Christina , Kerjaschki Dontscho , Rettig Wolfgang J. , Adolf Guenther R.
Published: July 2008

Purpose: Invasion and metastasis of malignant epithelial cells into normal tissues is accompanied by adaptive changes in the mesenchyme-derived supporting stroma of the target organs. Altered gene expression in these nontransformed stromal cells provides potential targets for therapy. The present study was undertaken to determine the antitumor effects of an antibody-conjugate against fibroblast activation protein-α, a cell surface protease of activated tumor fibroblasts.

Experimental Design: A novel antibody-maytansinoid conjugate, monoclonal antibody (mAb) FAP5-DM1, was developed to target a shared epitope of human, mouse, and cynomolgus monkey fibroblast activation protein-α, enabling preclinical efficacy and tolerability assessments. We have used stroma-rich models in immunodeficient mice, which recapitulate the histotypic arrangement found in human epithelial cancers.

Results: Treatment with mAb FAP5-DM1 induced long-lasting inhibition of tumor growth and complete regressions in xenograft models of lung, pancreas, and head and neck cancers with no signs of intolerability. Analysis of chemically distinct conjugates, resistance models, and biomarkers implicates a unique mode of action, with mitotic arrest and apoptosis of malignant epithelial cells coupled to disruption of fibroblastic and vascular structures.

Conclusions: We show that mAb FAP5-DM1 combines excellent efficacy and tolerability and provides a first assessment of the mode of action of a novel drug candidate for tumor stroma targeting, thus encouraging further development toward clinical testing of this treatment paradigm.
Statin-Dependent Suppression of the Akt/Mammalian Target of Rapamycin Signaling Cascade and Programmed Cell Death 4 Up-Regulation in Renal Cell Carcinoma
Authors: Woodard Jennifer , Sassano Antonella , Hay Nissim , Platanias Leonidas C.
Published: July 2008

Purpose: Statins are pharmacologic inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase with potent regulatory effects on cholesterol biosynthesis in vitro and in vivo. There is accumulating evidence that, beyond their cholesterol-lowering properties, statins inhibit cell proliferation and promote apoptosis of malignant cells in vitro, but the mechanisms by which they generate such responses remain to be defined.

Experimental Design: Combinations of experimental approaches were used, including immunoblotting and cell proliferation and apoptosis assays.

Results: We provide evidence that fluvastatin is a potent inducer of apoptosis and suppresses proliferation of renal cell carcinoma (RCC) cells in vitro. Such effects are mediated by direct targeting of the Akt/mammalian target of rapamycin (mTOR) pathway, as evidenced by the suppression of phosphorylation/activation of Akt, resulting in inhibition of its downstream effectors, mTOR and p70 S6 kinase. In addition, fluvastatin blocks the mTOR-dependent phosphorylation/deactivation of the translational repressor eukaryotic initiation factor 4E (eIF4E)-binding protein, leading to the formation of eIF4E-binding protein-eIF4E complexes that suppress initiation of cap-dependent mRNA translation. Importantly, inhibition of p70 S6 kinase activity by fluvastatin results in the up-regulation of expression of programmed cell death 4 (PDCD4), a tumor suppressor protein with inhibitory effects on the translation initiation factor eIF4A, suggesting a mechanism for the generation of antitumor responses.

Conclusions: Altogether, our findings establish that fluvastatin exhibits potent anti-RCC activities via inhibitory effects on the Akt/mTOR pathway and raise the possibility that combinations of statins and Akt inhibitors may be of future therapeutic value in the treatment of RCC.
Analysis and Reproducibility of 3′-Deoxy-3′-[18F]Fluorothymidine Positron Emission Tomography Imaging in Patients with Non–Small Cell Lung Cancer
Authors: Shields Anthony F. , Lawhorn-Crews Jawana M. , Briston David A. , Zalzala Sajad , Gadgeel Shirish , Douglas Kirk A. , Mangner Thomas J. , Heilbrun Lance K. , Muzik Otto
Published: July 2008

Purpose: Imaging tumor proliferation with 3′-deoxy-3′-[18F]fluorothymidine (FLT) and positron emission tomography is being developed with the goal of monitoring antineoplastic therapy. This study assessed the methods to measure FLT retention in patients with non-small cell lung cancer (NSCLC) to measure the reproducibility of this approach.

Experimental Design: Nine patients with NSCLC who were untreated or had progressed after previous therapy were imaged twice using FLT and positron emission tomography within 2 to 7 days. Reproducibility (that is, error) was measured as the percent difference between the two patient scans. Dynamic imaging was obtained during the first 60 min after injection. Activity in the blood was assessed from aortic images and the fraction of unmetabolized FLT was measured. Regions of interest were drawn on the plane with the highest activity and the adjacent planes to measure standardized uptake value (SUVmean) and kinetic variables of FLT flux.

Results: We found that the SUVmean obtained from 30 to 60 min had a mean error of 3.6% (range, 0.6-6.9%; SD, 2.3%) and the first and second scans were highly correlated (r2 = 0.99; P < 0.0001). Using shorter imaging times from 25 to 30 min or from 55 to 60 min postinjection also resulted in small error rates; SUVmean mean errors were 8.4% and 5.7%, respectively. Compartmental and graphical kinetic analyses were also fairly reproducible (r2 = 0.59; P = 0.0152 and r2 = 0.58; P = 0.0175 respectively).

Conclusion: FLT imaging of patients with NSCLC was quite reproducible with a worst case SUVmean error of 21% when using a short imaging time.
Visualization of Circulating Melanoma Cells in Peripheral Blood of Patients with Primary Uveal Melanoma
Authors: Ulmer Anja , Beutel Julia , Süsskind Daniela , Hilgers Ralf-Dieter , Ziemssen Focke , Lüke Matthias , Röcken Martin , Rohrbach Martin , Fierlbeck Gerhard , Bartz-Schmidt Karl-Ulrich , Grisanti Salvatore
Published: July 2008

Purpose: In patients with uveal melanoma, tumor cell dissemination and subsequent formation of metastases are confined mainly to the hematogenous route. Here, we sought to isolate circulating melanoma cells in peripheral blood of patients with primary uveal melanoma and clinically localized disease.

Experimental Design: Blood samples from 52 patients with clinically localized uveal melanoma and from 20 control individuals were prospectively collected before therapy of the primary tumor. Tumor cells expressing the melanoma-associated chondroitin sulfate proteoglycan were enriched by immunomagnetic cell sorting and visualized by immunocytologic staining. Results were compared with clinical data at presentation.

Results: In 10 of 52 patients [19%; 95% confidence interval (95% CI), 10-33%], between 1 and 5 circulating melanoma cells were detected in 50 mL peripheral blood. No melanoma-associated chondroitin sulfate proteoglycan–positive cells were detected in any of the 20 controls examined. The presence of tumor cells in peripheral blood was associated with ciliary body invasion [odds ratio (OR), 20.0; 95% CI, 3.0-131.7], advanced local tumor stage (OR, 6.7; 95% CI, 1.8-25.4), and anterior tumor localization (OR, 4.0; 95% CI, 1.2-12.7), all established factors for uveal melanoma progression.

Conclusions: Immunomagnetic enrichment enables detection of intact melanoma cells in peripheral blood of patients with clinically localized ocular disease. Visualization and capturing of these cells provide a unique tool for characterizing potentially metastasizing tumor cells from a primary melanoma at an early stage of the disease.
Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer
Authors: Dhillon Navneet , Aggarwal Bharat B. , Newman Robert A. , Wolff Robert A. , Kunnumakkara Ajaikumar B. , Abbruzzese James L. , Ng Chaan S. , Badmaev Vladimir , Kurzrock Razelle
Published: July 2008

Purpose: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration–approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-κB (NF-κB) and tumor inhibitory properties, against advanced pancreatic cancer.

Experimental Design: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-κB and cyclooxygenase-2 were monitored.

Results: Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-κB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks.

Conclusions: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.
Prevention and Treatment of Experimental Estrogen Receptor–Negative Mammary Carcinogenesis by the Synthetic Triterpenoid CDDO-Methyl Ester and the Rexinoid LG100268
Authors: Liby Karen , Risingsong Renee , Royce Darlene B. , Williams Charlotte R. , Yore Mark M. , Honda Tadashi , Gribble Gordon W. , Lamph William W. , Vannini Nicola , Sogno Ilaria , Albini Adriana , Sporn Michael B.
Published: July 2008

Purpose: To test whether the triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and the rexinoid LG100268 (268) prevent the formation of estrogen receptor (ER)–negative mammary tumors or either arrest the growth or cause regression of established tumors in MMTV-neu mice.

Experimental Design: For prevention, mice were fed control diet, CDDO-Me (60 mg/kg diet), 268 (20 mg/kg diet), or the combination for 45 weeks. For treatment, mice with established tumors at least 4 mm in diameter were fed control diet, CDDO-Me (100 mg/kg diet), 268 (60 mg/kg diet), or the combination for 4 weeks.

Results: CDDO-Me and 268 significantly delayed the development of ER-negative tumors, with a 14- and 24-week delay, respectively, compared with the control group for the time required to reach 50% tumor incidence. The combination of CDDO-Me and 268 was significantly more potent than the individual drugs, as only one tumor was found in the combination group, after 45 weeks on diet, at which time all control animals had tumors. Treating established tumors with CDDO-Me arrested the growth of 86% of the tumors, and 268 induced tumor regression in 85% of tumors. CDDO-Me and 268 target different signaling pathways and cell types. CDDO-Me inhibited constitutive STAT3 phosphorylation and the degradation of IKBα in ER-negative breast cancer cells, whereas 268 blocked IKBα degradation and the release of interleukin-6 in RAW264.7 macrophage-like cells, inhibited the ability of endothelial cells to organize into networks, and blocked angiogenesis in vivo.

Conclusions: CDDO-Me and 268 are useful as individual drugs to prevent ER-negative mammary tumorigenesis and to treat established tumors. They synergize when used in combination for prevention.
Therapeutic Consequences from Molecular Biology for Gastrointestinal Stromal Tumor Patients Affected by Neurofibromatosis Type 1
Authors: Mussi Chiara , Schildhaus Hans-Ulrich , Gronchi Alessandro , Wardelmann Eva , Hohenberger Peter
Published: July 2008

Purpose: Patients affected by neurofibromatosis type 1 (NF-1) have an increased risk of developing gastrointestinal stromal tumors (GIST). NF-1–associated GISTs are usually wild type for c-KIT and platelet-derived growth factor receptor-α (PDGFR-α) mutations and harbor a different oncogenic molecular mechanism. The lack of data on imatinib activity raises the question whether to enroll these patients in clinical trials. We analyzed a large series of NF-1 related GISTs to discuss the therapeutic implications.

Materials and Methods: Clinical, pathologic (IHC to CD34, S100, bcl-2, PDGFRA), and molecular features (exons 9, 11, 13, 14, 17 in c-kit and exons 12, 14, 18 in PDGFRA) of 28 patients were analyzed.

Results: The most common site of primary lesions was the small bowel (75%). Twelve patients (43%) had multiple tumors. Most tumors belonged to the high (30.5%) or intermediate risk group for malignant behavior (39%). Three patients developed peritoneal and liver metastases; another four had peritoneal spread only. All tumors were immunohistochemically strongly positive for CD117. Three primary KIT/PDGFRA activating mutations were found. Three metastatic patients treated with imatinib experienced progression, and only one had temporary stable disease. Median survival after starting treatment with imatinib was 21 months.

Conclusions: This study is the largest series available and confirms that KIT/PDGFRA mutations in NF-1–associated GISTs are sporadic. Prognosis of metastatic tumors is poor, and imatinib response rate is low. Patients with NF-1–GIST of high or intermediate risk should not be eligible for adjuvant trials of imatinib. Imatinib should not be used in a neoadjuvant intent in these patients, and molecular analysis of activating mutations is strongly recommended.
A Novel Recombinant Soluble Splice Variant of Met Is a Potent Antagonist of the Hepatocyte Growth Factor/Scatter Factor-Met Pathway
Authors: Tiran Zohar , Oren Anat , Hermesh Chen , Rotman Galit , Levine Zurit , Amitai Hagit , Handelsman Tal , Beiman Merav , Chen Aviva , Landesman-Milo Dalit , Dassa Liat , Peres Yair , Koifman Cynthia , Glezer Sarit , Vidal-Finkelstein Rinat , Bahat Kobi , Pergam Tania , Israel Cylia , Horev Judith , Tsarfaty Ilan , Ayalon-Soffer Michal
Published: July 2008

Purpose: The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), are involved in a wide range of biological activities, including cell proliferation, motility, invasion, and angiogenesis. The HGF/SF-Met signaling pathway is frequently activated in a variety of cancers, and uncontrolled Met activation correlates with highly invasive tumors and poor prognosis. In this study, we investigated the inhibitory effect of a novel soluble splice variant of Met on the HGF/SF-Met pathway.

Experimental Design: Using our alternative splicing modeling platform LEADS, we have identified a novel splice variant of the Met receptor, which encodes a truncated soluble form of the receptor. This variant was produced as a recombinant Fc-fused protein named Cgen-241A and was tested in various cell-based assays representing different outcomes of the HGF/SF-Met pathway.

Results: Cgen-241A significantly inhibited HGF/SF-induced Met phosphorylation as well as cell proliferation and survival. In addition, Cgen-241A showed a profound inhibitory effect on cell scattering, invasion, and urokinase up-regulation. The inhibitory effects of Cgen-241A were shown in multiple human and nonhuman cell types, representing different modes of Met activation. Furthermore, Cgen-241A showed direct binding to HGF/SF.

Conclusions: Taken together, our results indicate that Cgen-241A is a potent antagonist of the HGF/SF-Met pathway, underlining its potential as a therapeutic agent for the treatment of a wide variety of human malignancies that are dependent on this pathway.
Penetrance Analysis of the PALB2 c.1592delT Founder Mutation
Authors: Erkko Hannele , Dowty James G. , Nikkilä Jenni , Syrjäkoski Kirsi , Mannermaa Arto , Pylkäs Katri , Southey Melissa C. , Holli Kaija , Kallioniemi Anne , Jukkola-Vuorinen Arja , Kataja Vesa , Kosma Veli-Matti , Xia Bing , Livingston David M. , Winqvist Robert , Hopper John L.
Published: July 2008

Purpose: PALB2 is a recently identified breast cancer susceptibility gene. We have previously identified in the Finnish population a PALB2 c.1592delT founder truncation mutation that is associated with an increased risk of breast cancer. In the present study, we wanted to assess in more detail the increased risk (hazard ratio, HR) and the age-specific cumulative risk (penetrance) of c.1592delT with regard to susceptibility to breast and other forms of cancer.

Experimental Design: Modified segregation analyses fitted under maximum likelihood theory were used to estimate age-specific cumulative risks and HRs using the families of mutation carriers identified from a consecutive series of breast cancer cases unselected for age at onset or family history.

Results: We found a substantially increased risk of breast cancer [HR, 6.1; 95% confidence interval (95% CI), 2.2-17.2; P = 0.01] equivalent to a 40% (95% CI, 17-77) breast cancer risk by age 70 years, comparable to that for carriers of mutations in BRCA2. We found marginal evidence (P = 0.06) that the HR for breast cancer decreased with age by 4.2% per year (95% CI, 0.2-8.1), from 7.5-fold at age 30 years to 2.0-fold at age 60 years.

Conclusions: Our results suggest that it may be appropriate to offer PALB2 c.1592delT mutation testing to Finnish women with breast cancer, especially those with an early age at onset or a family history of breast or related cancers, and to offer carriers the option of participation in extended disease surveillance programs.
Randomized Phase III Clinical Trial Designs for Targeted Agents
Authors: Hoering Antje , LeBlanc Mike , Crowley John J.
Published: July 2008

Purpose: Cancer therapies with mechanisms of action which are very different from the more conventional chemotherapies are now being developed. In this article, we investigate the performance of several phase III clinical trial designs, both for testing the overall efficacy of a targeted agent and for testing its efficacy in a subgroup of patients with a tumor marker present. We study different designs and different underlying scenarios assuming continuous markers, and assess the trade-off between the number of patients on the study and the effectiveness of treatment in the subgroup of marker-positive patients.

Experimental Design: We investigate binary outcomes and use simulation studies to determine sample size and power for the different designs and the various scenarios. We also simulate marker prevalence and marker misclassification and evaluate their effect on power and sample size.

Results: In general, a targeted design which randomizes patients with the appropriate marker status performs the best in all scenarios with an underlying true predictive marker. Randomizing all patients regardless of their marker values performs as well as or better in most cases than a clinical trial that randomizes the patient to a treatment strategy based on marker value versus standard of care.

Conclusion: If there is the possibility that the new treatment helps marker-negative patients, or that the cutpoint determining marker status has not been well established and the marker prevalence is large enough, we recommend randomizing all patients regardless of marker values, but using a design such that both the overall and the targeted subgroup hypothesis can be tested.
Multi-Arm Clinical Trials of New Agents: Some Design Considerations
Authors: Freidlin Boris , Korn Edward L. , Gray Robert , Martin Alison
Published: July 2008

A major challenge in the development of anticancer therapies is the considerable time and resources needed for conducting randomized clinical trials (RCT). There is a need for more efficient RCT designs that accelerate development, minimize costs, and make trials more appealing to patients. We review the statistical and logistical characteristics of multi-arm designs that compare several experimental treatments to a common control arm. In particular, we present a rationale for not requiring multiplicity adjustment in multi-arm trials that are designed for logistical efficiency. Relative to conducting separate RCTs for each experimental agent, this multi-arm design is shown to require a lower total sample size than multiple two-arm trials.
Anti-invasive and Antimetastatic Activities of Ribosomal Protein S6 Kinase 4 in Breast Cancer Cells
Authors: Thakur Archana , Sun Yuan , Bollig Aliccia , Wu Jack , Biliran Hector , Banerjee Sanjeev , Sarkar Fazlul H. , Liao D. Joshua
Published: July 2008

Purpose: We have previously shown that p90 ribosomal protein S6 kinase 4 (RSK4), an X-linked gene, is highly up-regulated in mammary tumors of MMTV-c-Myc transgenic mice. In this study, we further investigated whether RSK4 inhibits or promotes breast tumor growth and progression.

Experimental Design: Stable overexpression or small interfering RNA–mediated knockdown of RSK4 was done in the MDA-MB-231 cell line. Stable clones were tested for cell proliferation, anchorage-independent growth in soft agar, invasive and metastatic ability of these clones in vitro and tumorigenesis, invasive and metastatic ability in vivo in severe combined immunodeficient mice.

Results: Here, we show that exogenous expression of RSK4 resulted in decreased cell proliferation and increased accumulation of cells in G0-G1 phase, which paralleled with enhanced expression of tumor suppressor genes: retinoblastoma protein, retinobl astoma-associated 46 kDa protein, and p21 protein. Overexpression of RSK4 resulted in reduced colony formation in soft agar and suppressed invasive and migratory activities of MDA-MB-231 cells both in vitro and in vivo. Importantly, RSK4-overexpressing cells showed up-regulation of claudin-2 and down-regulation of CXCR4, both of these play roles in invasion and chemotaxis.

Conclusions: These results indicate that RSK4 expression may limit the oncogenic, invasive, and metastatic potential of breast cancer cells. Anti-invasive and antimetastatic activities of RSK4 may be, in part, due to its regulation of claudin-2. Increased expression of RSK4 in c-Myc-overexpressing cells and a dose-dependent induction of luciferase reporter gene activity suggest that c-Myc may regulate RSK4 expression.
Fragmented Wide QRS on a 12-Lead ECG
Authors: Das Mithilesh K. , Suradi Hussam , Maskoun Waddah , Michael Mark A. , Shen Changyu , Peng Jonathan , Dandamudi Gopi , Mahenthiran Jo
Published: July 2008

Background—

Fragmented QRS (duration <120 ms) on a 12-lead ECG represents myocardial scar in patients with coronary artery disease. However, the significance of fragmented QRS has not been defined in the presence of a wide QRS (wQRS; duration ≥120 ms). We postulate that fragmented wQRS (f-wQRS) due to bundle branch block, premature ventricular complexes, or paced rhythms (f-pQRS) signify myocardial scar and higher mortality.

Methods and Results—

Patients who underwent cardiac evaluation with nuclear stress imaging or cardiac catheterization and had wQRS (bundle branch block, premature ventricular complex, or pQRS) were studied. f-wQRS was defined by the presence of >2 notches on the R wave or the S wave and had to be present in ≥2 contiguous inferior (II, III, aVF), lateral (I, aVL, V
6
) or anterior (V
1
to V
5
) leads. ECG analyses of 879 patients (age, 66.7�11.4 years; male, 97%; mean follow-up, 29�18 months) with bundle branch block (n=310), premature ventricular complex (n=301), and pQRS (n=268) revealed f-wQRS in 415 (47.2%) patients. Myocardial scar was present in 440 (50%) patients. The sensitivity, specificity, positive predictive value, and negative predictive value of f-wQRS for myocardial scar were 86.8%, 92.5%, 92.0%, and 87.5%, respectively. The sensitivity and specificity for diagnosing myocardial scar were 88.6% and 94.4%, 81.4% and 88.4%, and 89.8% and 95.7% for f-bundle branch block, f-premature ventricular complex, and f-pQRS, respectively. f-wQRS was associated with mortality after adjusting for age, ejection fraction, and diabetes (
P
=0.017).

Conclusions—

f-wQRS on a standard 12-lead ECG is a moderately sensitive and highly specific sign for myocardial scar in patients with known or suspected coronary artery disease. f-wQRS is also an independent predictor of mortality.
Chronic Glucagon-Like Peptide-1 Infusion Sustains Left Ventricular Systolic Function and Prolongs Survival in the Spontaneously Hypertensive, Heart Failure–Prone Rat
Authors: Poornima Indu , Brown Suzanne B. , Bhashyam Siva , Parikh Pratik , Bolukoglu Hakki , Shannon Richard P.
Published: July 2008

Background—

Glucagon-like peptide-1 (GLP-1) treatment leads to short-term improvements in myocardial function in ischemic and nonischemic cardiomyopathy. It is unknown whether GLP-1 improves survival when administered over a longer time period. Spontaneously hypertensive, heart failure–prone (SHHF) rats progress to advanced heart failure and death over a 15-month period. The authors sought to determine whether a continuous infusion of GLP-1 would reduce mortality in this model.

Methods and Results—

At 9 months of age, 50 SHHF rats were randomized to receive a 3-month, continuous infusion of either GLP-1 or saline. Metabolic parameters were measured and cardiac ultrasounds performed at study initiation and completion of treatment. Surviving rats were euthanized at 12 months. Hearts were perfused in an isolated, isovolumic heart preparation, and Tunel staining of myocardial samples was performed. Baseline metabolic and cardiac functional parameters were comparable. GLP-1–treated SHHF rats had greater survival (72% versus 44%,
P
=0.008) at 12 months of age. In addition, GLP-1 treatment led to higher plasma insulin, lower plasma triglycerides, and preserved left ventricular (LV) function. GLP-1–treated rats demonstrated decreased myocyte apoptosis by Tunel staining as well as reduced caspase-3 activation. No increase in p-BAD expression was seen. In isolated hearts, the LV systolic pressure and LV-developed pressure were greater in the GLP-1 group. Myocardial glucose uptake was also increased in GLP-1–treated SHHF rats.

Conclusions—

Chronic GLP-1 treatment prolongs survival in obese SHHF rats. This is associated with preserved LV function and LV mass index, increased myocardial glucose uptake, and reduced myocyte apoptosis.
Does Sodium Nitroprusside Decrease the Incidence of Atrial Fibrillation After Myocardial Revascularization?
Authors: Cavolli Raif , Kaya Kaan , Aslan Alp , Emiroglu Ozan , Erturk Sebnem , Korkmaz Ozge , Oguz Mehmet , Tasoz Refik , Ozyurda Umit
Published: July 2008

Background—

Atrial fibrillation (AF) often occurs after coronary artery bypass grafting and can result in increased morbidity and mortality. In the present pilot study, our aim was to investigate whether sodium nitroprusside (SNP), as a nitric oxide donor, can reduce the frequency of post–coronary artery bypass grafting AF.

Methods and Results—

To investigate the effectiveness of SNP in the prophylaxis of AF, we conducted a prospective, randomized, placebo-controlled clinical study on 100 consecutive patients in whom we performed elective and initial CABG operations. A control group of 50 patients were treated with placebo (dextrose 5% in water), whereas the SNP group (n=50 patients) was treated with SNP (0.5 μg · kg
−1
· min
−1
) during the rewarming period. High-sensitivity C-reactive protein levels were measured before surgery and 5 days postoperatively. All patients were monitored postoperatively with telemetry. Baseline characteristics were similar in both treatment groups. AF occurred in 12% of the SNP group and 27% of the control group. The occurrence of AF was significantly lower in the SNP group (
P
=0.005). The duration of AF in the SNP group was significantly shorter than that in the control group (5.33±1.86 and 7.55±1.94 hours, respectively;
P
=0.023). C-reactive protein levels were higher postoperatively in the control group than in the SNP group (
P
<0.05). Postoperative AF significantly prolonged postoperative hospital stay (
P
<0.05).

Conclusions—

The incidence of postoperative AF in the SNP group was reduced significantly. Further studies are needed to better delineate the anti-AF profile of SNP.
Evidence of Arteriolar Narrowing in Low-Birth-Weight Children
Authors: Mitchell Paul , Liew Gerald , Rochtchina Elena , Wang Jie Jin , Robaei Dana , Cheung Ning , Wong Tien Y.
Published: July 2008

Background—

Cardiovascular disease may have its origins in utero, but the influence of in utero growth on microvascular structure in children is unknown. We hypothesized that poor in utero growth is associated with narrower arteriolar caliber, which may help explain the established association of low birth weight with hypertension and cardiovascular disease in adulthood.

Methods and Results—

We examined the relation of birth weight and other markers of in utero growth to microvascular caliber in the retina in a population-based study of 1369 6-year-old children in Sydney, Australia (Sydney Childhood Eye Study). Birth weight, birth length, and head circumference were obtained from parental records. Retinal arteriolar and venular calibers were measured from digitized retinal photographs by a validated computer-assisted method. Lower birth weight, shorter birth length, and smaller head circumference were associated with narrower retinal arteriolar caliber. Each kilogram decrease in birth weight was associated with a 2.3-μm (95% CI 0.6 to 3.9,
P
=0.01) narrower retinal arteriolar caliber after controlling for age, gender, ethnicity, height, body mass index, axial length, mean arterial blood pressure, and prematurity. Similar associations were observed between shorter birth length and smaller head circumference with narrower retinal arteriolar caliber.

Conclusions—

Children who had lower birth weight, shorter birth length, and smaller head circumference had narrower retinal arteriolar calibers. These data support the concept that poor in utero growth may have an adverse influence on microvascular structure.
Relation Between Body Mass Index, Waist Circumference, and Death After Acute Myocardial Infarction
Authors: Zeller Marianne , Steg Philippe Gabriel , Ravisy Jack , Lorgis Luc , Laurent Yves , Sicard Pierre , Janin-Manificat Luc , Beer Jean-Claude , Makki Hamid , Lagrost Anne-Cécile , Rochette Luc , Cottin Yves
Published: July 2008

Background—

An elevated body mass index (BMI) has been reported to be associated with a lower rate of death after acute myocardial infarction (AMI). However, waist circumference (WC) may be a better marker of cardiovascular risk than BMI. We used data from a contemporary French population-based cohort of patients with AMI to analyze the impact of WC and BMI on death rates.

Methods and Results—

We evaluated 2229 consecutive patients with AMI. Patients were classified according to BMI as normal, overweight, obese, and very obese (BMI <25, 25 to 29.9, 30 to 34.5, and >35 kg/m
2
, respectively) and as increased waistline (WC >88/102 cm for women/men) or normal. Half of the patients were overweight (n=1044), and one quarter were obese (n=397) or very obese (n=128). Increased WC was present in half of the patients (n=1110). Increased BMI was associated with a reduced death rate, with a 5% risk reduction for each unit increase in BMI (hazard ratio, 0.95; 95% CI, 0.93 to 0.98;
P
<0.001). In contrast, WC as a continuous variable had no impact on all-cause death (
P
=0.20). After adjustment for baseline predictors of death, BMI was not independently predictive of death. The group of patients with high WC but low BMI had increased 1-year death rate.

Conclusions—

Neither BMI nor WC independently predicts death after AMI. Much of the inverse relationship between BMI and the rate of death after AMI is due to confounding by characteristics associated with survival. This study emphasizes the need to measure both BMI and WC because patients with a high WC and low BMI are at high risk of death.
Translating Research Into Practice for Healthcare Providers
Authors: Jones Daniel W. , Peterson Eric D. , Bonow Robert O. , Masoudi Frederick A. , Fonarow Gregg C. , Smith Sidney C. , Solis Penelope , Girgus Meighan , Hinton Patricia C. , Leonard Anne , Gibbons Raymond J.
Published: July 2008

The American Heart Association’s (AHA’s) mission is “to build healthier lives, free of cardiovascular diseases and stroke.” This first article in a 2-part series will serve to present an overview of the work the AHA has undertaken to translate evidence into practice for healthcare professionals. It describes the extensive work of the AHA to support and further the delivery of evidence-based medicine, which includes the following: (1) supporting scientific discovery and the next generation of healthcare professionals and researchers; (2) disseminating scientific information; (3) developing evidence-based guidelines and statements; (4) creating and advocating for the implementation of performance indicators/measures; (5) developing clinical decision support and quality improvement tools; and (6) developing directed-cause campaigns, all of which can lead to improved patient care. This article also discusses the need for novel approaches and some of the AHA’s evolving strategies to help address gaps in care. The second article, which will be published shortly after this one, will examine the AHA’s efforts to engage and empower healthcare consumers to become more involved with their own health and health care.
Generation of Functional Murine Cardiac Myocytes From Induced Pluripotent Stem Cells
Authors: Mauritz Christina , Schwanke Kristin , Reppel Michael , Neef Stefan , Katsirntaki Katherina , Maier Lars S. , Nguemo Filomain , Menke Sandra , Haustein Moritz , Hescheler Juergen , Hasenfuss Gerd , Martin Ulrich
Published: July 2008

Background—

The recent breakthrough in the generation of induced pluripotent stem (iPS) cells, which are almost indistinguishable from embryonic stem (ES) cells, facilitates the generation of murine disease– and human patient–specific stem cell lines. The aim of this study was to characterize the cardiac differentiation potential of a murine iPS cell clone in comparison to a well-established murine ES cell line.

Methods and Results—

With the use of a standard embryoid body–based differentiation protocol for ES cells, iPS cells as well as ES cells were differentiated for 24 days. Although the analyzed iPS cell clone showed a delayed and less efficient formation of beating embryoid bodies compared with the ES cell line, the differentiation resulted in an average of 55% of spontaneously contracting iPS cell embryoid bodies. Analyses on molecular, structural, and functional levels demonstrated that iPS cell–derived cardiomyocytes show typical features of ES cell–derived cardiomyocytes. Reverse transcription polymerase chain reaction analyses demonstrated expression of marker genes typical for mesoderm, cardiac mesoderm, and cardiomyocytes including Brachyury, mesoderm posterior factor 1 (Mesp1), friend of GATA2 (FOG-2), GATA-binding protein 4 (GATA4), NK2 transcription factor related, locus 5 (Nkx2.5), T-box 5 (Tbx5), T-box 20 (Tbx20), atrial natriuretic factor (ANF), myosin light chain 2 atrial transcripts (MLC2a), myosin light chain 2 ventricular transcripts (MLC2v), α-myosin heavy chain (α-MHC), and cardiac troponin T in differentiation cultures of iPS cells. Immunocytology confirmed expression of cardiomyocyte-typical proteins including sarcomeric α-actinin, titin, cardiac troponin T, MLC2v, and connexin 43. iPS cell cardiomyocytes displayed spontaneous rhythmic intracellular Ca
2+
fluctuations with amplitudes of Ca
2+
transients comparable to ES cell cardiomyocytes. Simultaneous Ca
2+
release within clusters of iPS cell–derived cardiomyocytes indicated functional coupling of the cells. Electrophysiological studies with multielectrode arrays demonstrated functionality and presence of the β-adrenergic and muscarinic signaling cascade in these cells.

Conclusions—

iPS cells differentiate into functional cardiomyocytes. In contrast to ES cells, iPS cells allow derivation of autologous functional cardiomyocytes for cellular cardiomyoplasty and myocardial tissue engineering.
Shift Work Is a Risk Factor for Increased Blood Pressure in Japanese Men
Authors: Suwazono Yasushi , Dochi Mirei , Sakata Kouichi , Okubo Yasushi , Oishi Mitsuhiro , Tanaka Kumihiko , Kobayashi Etsuko , Nogawa Koji
Published: July 2008

To clarify the effect of shift work on blood pressure in Japanese men, a 14-year historical cohort study was conducted in day workers (n=3963) and alternating shift workers (n=2748) who received annual health checkups between 1991 and 2005 in a Japanese steel company. The end points were a ≥10%, ≥15%, ≥20%, ≥25%, or ≥30% increase in systolic blood pressure or diastolic blood pressure from baseline during the period of observation. The association between shift work and an increase in blood pressure was investigated adjusting for age, body mass index, hemoglobin A1c, total serum cholesterol, creatinine, aspartate aminotransferase, γ-glutamyl transpeptidase, uric acid, drinking habit, smoking habit, and habitual exercise by multivariate pooled logistic regression analyses. Shift work was significantly associated with the various end points. The odds ratios (and 95% CIs) were as follows: ≥10%, 1.15 (1.07 to 1.23); ≥15%, 1.21 (1.12 to 1.31); ≥20%, 1.15 (1.04 to 1.28); ≥25%, 1.20 (1.06 to 1.37); and ≥30%, 1.23 (1.03 to 1.47) for systolic blood pressure and ≥10%, 1.19 (1.11 to 1.28); ≥15%, 1.22 (1.13 to 1.33); ≥20%, 1.24 (1.13 to 1.37); and ≥25%, 1.16 (1.03 to 1.30) for diastolic blood pressure. Our study in male Japanese workers revealed that alternating shift work was a significant independent risk factor for an increase in blood pressure. Moreover, the effect of shift work on blood pressure was more pronounced than other well-established factors, such as age and body mass index.
Children's Participation and Good Governance: Limitations of the Theoretical Literature
Authors: Hinton Rachel
Published: July 2008

Children are an important stakeholder group; they constitute 34% of the world's citizens and their actions will determine our collective future. The UNCRC created consensus that children's views must be taken seriously. Yet their opinions have failed to inform the allocation of resources used in their name. Their views are rarely sought during scrutiny of government despite their valuable insights on the functioning of public institutions. This paper summarises the debates around children's participation and argues that there has been little dialogue across the academic fields. The long history of children's participation in the South is only starting to inform the new wave of attention to children as active citizens in the North. The paper poses questions as a catalyst for further debate: Why do theoretical frameworks fail children? What is the impact of the process of 'participation'? Are children who lack the networks and social capital being excluded?
Children's Participation in Brazil – A Brief Genealogy and Recent Innovations
Authors: Mandel Butler Udi
Published: July 2008

This paper provides an overview of significant developments in Brazil in regard to children and young people's rights and participation in the public sphere. The paper addresses the importance of historically contextualizing particular practices and policies towards children and young people, in order to understand present manifestations of their "participation". Outlining the Brazilian context of deep inequality, the paper reflects how different childhoods, that of the rich and of the poor, have been differently categorised and acted upon. The paper goes on to give an account of the important movements of mass participation that emerged through the 1970s, in particular those concerning Popular Education, that sought to dismantle repressive institutions and relationships within the country, including those towards the children of the poorest sectors of the population. Important here is the influence of Brazilian pedagogue and activist Paulo Freire, whose ideas around 'conscientization' and their subsequent impact on participatory practices with children and young people are also addressed. The paper concludes with a brief overview of recent research on the multiple spaces of participation young people are engaged in, offering some possible avenues for future research.
Reflecting on Children and Young People's Participation in the UK
Authors: Gallagher Michael , M. Tisdall Kay , Davis John
Published: July 2008

The article interrogates how children and young people's participation in public decision-making has been promoted in the UK. It considers critically the reasons typically (and persuasively) put forward for such participation, which can be categorized as: the promotion of children's rights; alignment with consumerism and service user involvement; enhancing democracy; and developing children's well-being and development. Each of these reasons can appeal to particular agendas of policy-makers, professionals and other influential adults, to provide room and support for participation. But inevitably each reason has certain advantages and disadvantages, acted out in current trends and accompanying dilemmas in children and young people's participation activities.
Learning from Political Sociology: Structure, Agency and Inclusive Governance
Authors: Gale Richard , O'Toole Therese
Published: July 2008

In this article, we consider the inclusion of children and young people in participatory governance processes. Whilst limitations are often evident in such processes, we argue that even participatory opportunities that are provided by the state and regarded as spaces into which citizens are invited can be "conquered by civil society demands for inclusion" (Cornwall and Coelho, 2006: 1). To this end, we suggest a practice-based and diachronic approach to studying the interactions between participatory structures and children and young people's agency. Being attentive to the agency of children and young people, and adopting a more diachronic approach to evaluating participatory initiatives, point to the possibility, we suggest, of seeing these relationships unfold in sometimes unexpected ways.
Children's Participation: Learning from and for Community Development
Authors: Percy-Smith Barry , Taylor Marilyn
Published: July 2008

Interest in children's participation has in the main come about as a result of the UNCRC. However, children's participation is also relevant to a wider global interest in citizen and community participation more generally. But there is surprisingly little sharing of experience and learning between the research communities concerned with children's participation on the one hand and community engagement and empowerment on the other. This article seeks to address that gap by reflecting on the learning from both of these traditions, drawing mainly on UK experience. It begins by outlining some of the key dilemmas and challenges facing children's participation. It then explores the parallels between that experience and the experience of community participation in New Labour's neighbourhood and democratic renewal programmes. It goes on to consider some theoretical tools for responding to the common dilemmas in both settings, before discussing the implications for children's participation. It ends by arguing that more attention to children's participation could benefit community engagement policy and practice more widely.
Foucault, Power and Participation
Authors: Gallagher Michael
Published: July 2008

In this paper, I argue that Foucault's work on power offers a distinctive and original perspective with the potential to afford insights into the nature of participation. I begin by providing a brief exegesis of Foucault's conceptualisation of power in his middle to late work. The notion of governmentality is drawn out as a potentially useful tool in understanding participation as a profoundly ambiguous phenomenon. I conclude by outlining some of the possible implications of Foucault's thinking about power for studying children's participation.
Is the Honeymoon Over? Children and Young People's Participation in Public Decision-Making
Authors: M. Tisdall Kay
Published: July 2008

Children and young people's participation in public decision-making is now firmly on international and national agendas. This article concludes the special issue on such participation, by discussing three central issues for children and young people's participation: what is counted – or discounted – as legitimate forms of participation; the potential usefulness of theorisations of governance, citizenship and social capital; and how the roles of adults (participation workers) can be understood. The article celebrates the success of the rhetorical push for children and young people's participation, while suggesting that the tensions and dilemmas of current practice and policy need to be addressed by new and revitalised ideas and challenging theorisations.
Excessive Growth
Authors: Narayanaswamy Vasudha , Rettig Kenneth R. , Bhowmick Samar K.
Published: July 2008

Tall stature and excessive growth syndrome are a relatively rare concern in pediatric practice. Nevertheless, it is important to identify abnormal accelerated growth patterns in children, which may be the clue in the diagnosis of an underlying disorder. We present a case of pituitary gigantism in a 2 1/2-year-old child and discuss the signs, symptoms, laboratory findings, and the treatment. Brief discussions on the differential diagnosis of excessive growth/tall stature have been outlined. Pituitary gigantism is very rare in the pediatrics age group; however, it is extremely rare in a child that is less than 3 years of age. The nature of pituitary adenoma and treatment options in children with this condition have also been discussed.
Initial Fluid Resuscitation for Patients With Diabetic Ketoacidosis: How Dry Are They?
Authors: Fagan Michele J. , Avner Jeffrey , Khine Hnin
Published: July 2008

A prospective consecutive case series of patients aged 5 to 20 years who presented to a pediatric emergency department with diabetic ketoacidosis (DKA) was studied to determine the actual percent loss of body weight during an episode of DKA to determine the degree of dehydration and thereby provide a guide for hydration therapy during such an episode. Patients' weights at the time of presentation, inpatient discharge, and at the first follow-up clinic visit were used to calculate the percent loss of body weight. Data from 33 episodes of DKA showed that the majority of patients with DKA had moderate (4% to 8%) dehydration. Clinical assessment was a poor predictor of severity of dehydration and overestimated the percent dehydration in 67% of patients. Based on these data it is recommend that initial fluid therapy for DKA should assume moderate dehydration with adjustment made according to clinical response.