bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of an Integrated SV40 T/t-Antigen Cancer Signature in Aggressive Human Breast, Prostate, and Lung Carcinomas with Poor Prognosis
Authors: Deeb Kristin K. , Michalowska Aleksandra M. , Yoon Cheol-yong , Krummey Scott M. , Hoenerhoff Mark J. , Kavanaugh Claudine , Li Ming-chung , Demayo Francesco J. , Linnoila Ilona , Deng Chu-xia , Lee Eva Y-H.P. , Medina Daniel , Shih Joanna H. , Green Jeffrey E.
Published: September 2007

Understanding the genetic architecture of cancer pathways that distinguishes subsets of human cancer is critical to developing new therapies that better target tumors based on their molecular expression profiles. In this study, we identify an integrated gene signature from multiple transgenic models of epithelial cancers intrinsic to the functions of the Simian virus 40 T/t-antigens that is associated with the biological behavior and prognosis for several human epithelial tumors. This genetic signature, composed primarily of genes regulating cell replication, proliferation, DNA repair, and apoptosis, is not a general cancer signature. Rather, it is uniquely activated primarily in tumors with aberrant p53, Rb, or BRCA1 expression but not in tumors initiated through the overexpression of myc, ras, her2/neu, or polyoma middle T oncogenes. Importantly, human breast, lung, and prostate tumors expressing this set of genes represent subsets of tumors with the most aggressive phenotype and with poor prognosis. The T/t-antigen signature is highly predictive of human breast cancer prognosis. Because this class of epithelial tumors is generally intractable to currently existing standard therapies, this genetic signature identifies potential targets for novel therapies directed against these lethal forms of cancer. Because these genetic targets have been discovered using mammary, prostate, and lung T/t-antigen mouse cancer models, these models are rationale candidates for use in preclinical testing of therapies focused on these biologically important targets. [Cancer Res 2007;67(17):8065–80]
Toll-like Receptor Ligands Energize Peptide Vaccines through Multiple Paths
Authors: Celis Esteban
Published: September 2007

The potential of vaccines for cancer therapy or prevention has yet to be realized. Recently, we showed that using an immunologic adjuvant composed of a Toll-like receptor (TLR) ligand can increase the production of antitumor CTLs produced by a peptide vaccine in a mouse model of breast cancer. By increasing the cross talk between the innate and adaptive immune systems, TLR ligands can drive expansion and memory of CTLs that can destroy cancer cells. [Cancer Res 2007;67(17):7945–7]
Meriolins, a New Class of Cell Death–Inducing Kinase Inhibitors with Enhanced Selectivity for Cyclin-Dependent Kinases
Authors: Bettayeb Karima , Tirado Oscar M. , Marionneau-Lambot Séverine , Ferandin Yoan , Lozach Olivier , Morris Jonathan C. , Mateo-Lozano Silvia , Drueckes Peter , Schächtele Christoph , Kubbutat Michael H.G. , Liger François , Marquet Bernard , Joseph Benoît , Echalier Aude , Endicott Jane A. , Notario Vicente , Meijer Laurent
Published: September 2007

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1α, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms. [Cancer Res 2007;67(17):8325–34]
Heterogeneity of TMPRSS2 Gene Rearrangements in Multifocal Prostate Adenocarcinoma: Molecular Evidence for an Independent Group of Diseases
Authors: Mehra Rohit , Han Bo , Tomlins Scott A. , Wang Lei , Menon Anjana , Wasco Matthew J. , Shen Ronglai , Montie James E. , Chinnaiyan Arul M. , Shah Rajal B.
Published: September 2007

Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS family transcription factors ERG, ETV1, and ETV4 have been identified in the majority of prostate adenocarcinomas (PCA). PCA is often multifocal with histologic heterogeneity of different tumor foci. As TMPRSS2 is a common 5′ partner of ETS gene fusions, we monitored TMPRSS2 rearrangement by fluorescence in situ hybridization (FISH) to study the origin and molecular basis of multifocal PCA heterogeneity. TMPRSS2 rearrangement was evaluated by FISH on a tissue microarray representing 93 multifocal PCAs from 43 radical prostatectomy resections. Overall, 70% (30 of 43) of the cases showed TMPRSS2 rearrangement, including 63% through deletion (loss of the 3′ TMPRSS2 signal), 27% through translocation (split of 5′ and 3′ TMPRSS2 signals), and 10% through both mechanisms in different tumor foci. Of the 30 TMPRSS2 rearranged cases, 30% showed concordance in all tumor foci, whereas 70% were discordant in at least one focus. In TMPRSS2 rearranged cases, the largest (index) tumor was rearranged 83% of the time. Pathologic stage, size, or Gleason grade of the multifocal PCA did not correlate with overall TMPRSS2 rearrangement. Our results suggest that multifocal PCA is a heterogeneous group of diseases arising from multiple, independent clonal expansions. Understanding this molecular heterogeneity is critical to the future development and utility of diagnostic and prognostic PCA biomarkers. [Cancer Res 2007;67(17):7991–5]
Thyroid-Stimulating Hormone–Initiated Proliferative Signals Converge In vivo on the mTOR Kinase without Activating AKT
Authors: Brewer Charlene , Yeager Nicole , Di Cristofano Antonio
Published: September 2007

Thyroid-stimulating hormone (TSH) has long been recognized as the major proliferative and functional stimulus for thyroid follicular cells. TSH receptor (TSHR) engagement stimulates the production of cyclic AMP and the subsequent activation of downstream effector molecules, including protein kinase A, S6K1, and Rap1, whereas the role of the RAS and phosphatidylinositol-3-kinase signaling cascades downstream of TSHR is still controversial. Despite the abundance of candidates, it is still unclear which of these pathways represent(s) the key mitogenic output of TSH-initiated signaling. We have used an in vivo model of goitrogenesis to dissect the contribution of these pathways to TSH-induced thyrocyte proliferation and thyroid hyperplasia. We show that the in vivo proliferative response to chronic TSHR stimulation relies heavily on the activation of the mTOR/S6K1 axis, and that mTOR inhibition during goitrogenic stimulation abrogates the hyperplastic but not the hypertrophic thyrocyte responses to TSH, thus functionally uncoupling these two processes. Strikingly, goitrogenesis was not associated with an increase in AKT phosphorylation levels, underlining the existence of an AKT-independent pathway leading to mTOR activation upon TSH stimulation. [Cancer Res 2007;67(17):8002–6]
Cervical Nerve Root Synovial Sarcoma in a Child with Chromosomal (X;18) Translocation
Authors: de Ribaupierre Sandrine , Vernet Olivier , Beck-Popovic Maya , Meagher-Villemure Kathleen , Rilliet Bénédict
Published: September 2007

We report on an 11-year-old female with a history of cervicobrachialgia and progressive weakness of the right arm. Cervical spine MRI showed an enhancing heterogeneous intradural mass occupying the right C6-C7 foramen. She underwent a right C6-C7 foraminotomy with a complete macroscopic removal of the lesion. Pathological examination revealed a synovial sarcoma. Treatment was completed by chemotherapy and proton radiotherapy, and the girl remained free of symptoms for 3 years. After appearance of new symptoms, a local recurrence was confirmed, and despite aggressive treatment with salvage chemotherapy and radiotherapy, the disease progressed beyond medical control, and the child died, 6 years after diagnosis. Early recognition of this rare entity compared to its more benign differential diagnosis is crucial, as an aggressive management is needed.
Posterior Fossa Syndrome after a Vermian Stroke: A New Case and Review of the Literature
Authors: Baillieux Hanne , Weyns Frank , Paquier Philippe , De Deyn Peter P. , Mariën Peter
Published: September 2007

The posterior fossa syndrome (PFS) is a well-known clinical consequence of posterior fossa surgery that has only been reported in a limited number of cases with a nontumoral etiology. It consists of transient cerebellar mutism, behavioral abnormalities and personality changes. We describe a 12-year-old child who developed transient cerebellar mutism associated with behavioral and emotional symptoms following rupture of a vermis arteriovenous malformation (AVM). Following the stroke, the girl experienced a 24-hour symptom-free interval. After that, she became mute and her emotional state was characterized by severe anxiety, irritability and withdrawal. After 3 days, mutism resolved and dysarthria became apparent. Two weeks after stroke, the AVM was surgically removed and the postoperative course was uneventful. This case is the first reported in which the PFS occurred after focal nonsurgically induced cerebellar damage.
Cerebrospinal Fluid Penetration and Bacteriostatic Activity of Linezolid against Enterococcus faecalis in a Child with a Ventriculoperitoneal Shunt Infection
Authors: Milstone Aaron M. , Dick James , Carson Benjamin , Siberry George K.
Published: September 2007

We report a 4-year-old girl with a complicated Enterococcus faecalis ventriculoperitoneal shunt infection who failed vancomycin therapy. We demonstrate linezolid’s high CSF penetration and its CSF bacteriostatic activity against E. faecalis. Linezolid may be a good alternative for treatment of ventriculoperitoneal shunt infections in cases of vancomycin-resistant organisms or apparent treatment failures.
Valve Pressure Upgrade May Produce Progressive Deterioration of Vision in Children with Slit Ventricle Syndrome
Authors: Park Seoung Woo , Yoon Soo Han , Cho Ki Hong , Shin Yong Sam
Published: September 2007

Recently, valve upgrade and/or endoscopic third ventriculostomy, which have the merit of no additional shunting, were introduced for the treatment of slit ventricle syndrome, because lumboperitoneal shunting entails various complications including development of Chiari malformation, shunt malfunction, and infection. However, the safety of valve upgrading is not confirmed, especially in a child with slit ventricle syndrome developed as a result of pseudotumor cerebri. A 5-year-old boy with pseudotumor cerebri presented with headache, intermittent vomiting, and sudden deterioration of visual acuity. His cerebrospinal pressure during lumbar puncture was 69 cm H2O and his magnetic resonance imaging revealed only small ventricles. He underwent a ventriculoperitoneal shunt resulting in dramatic improvement. Four months later, he returned with recurrent spontaneous valve malfunction with recurrent severe headache and visual deterioration. After shunt revision with a programmable valve, his intermittent valve malfunction was improved by upgrading the valve opening pressure. However, his visual acuity became progressively aggravated. He underwent a lumboperitoneal shunt with low-pressure valve, which resulted in the disappearance of intermittent headaches and a deterioration of visual acuity. We suggest that valve pressure upgrade in children with slit ventricle syndrome after ventriculoperitoneal shunt for pseudotumor cerebri may produce acute deterioration of vision that had already been compromised, even within the normal intracranial pressure range and with improvement of associated symptoms.
A Witnessed Short Fall Mimicking Presumed Shaken Baby Syndrome (Inflicted Childhood Neurotrauma)
Authors: Gardner Horace B.
Published: September 2007

A witnessed fall backwards of an infant from a sitting position resulted in the subdural hematoma and retinal hemorrhages characteristic of presumed shaken baby syndrome. Violent shaking is not necessary to produce these findings.
Identification of Natural Compounds with Anti-Hepatitis B Virus Activity from Rheum palmatum L. Ethanol Extract
Authors: Li Zhi , Li Li-jun , Sun Yan , Li Jing
Published: September 2007

Background: Hepatitis B virus (HBV) infection is a severe health problem in the world; however, there is still no satisfactory therapeutic strategy for the HBV infection. In search for new anti-HBV agents with higher efficiency and less side effects, the anti-HBV activities of traditional Chinese medicine Rheum palmatum L. ethanol extract (RPE) and isolated anthraquinones were evaluated. Methods: The anti-HBV activities of RPE and isolated anthraquinones were demonstrated in a stable HBV-producing cell line HepG2 2.2.15 by using real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA) and Southern blot analysis. Results: RPE could inhibit HBV-DNA production and HBsAg expression in a dose-dependent manner. The concentration of 50% HBV-DNA inhibition (IC50) of RPE was calculated at 212.36 ± 11 µg/ml. Six anthraquinones were isolated from RPE by using RP-HPLC. Five free anthraquinones showed weakly or slightly inhibitory activities against HBV. The only combined anthraquinone chrysophanol 8-O-β-D-glucoside exhibited significant activity against HBV DNA production and antigens expression with an IC50 value of 36.98 ± 2.28 µg/ml on HBV DNA inhibition. Endogenous HBV DNA polymerase activity assay indicated that chrysophanol 8-O-β-D-glucoside might be a potential inhibitor of the HBV DNA polymerase. Conclusions: The results suggested that RPE could effectively inhibit HBV. The combined anthraquinone chrysophanol 8-O-β-D-glucoside is the major active compound in RPE and could be a promising candidate for the development of new anti-HBV drugs in the treatment of HBV infection.
Witzel Catheter Feeding Jejunostomy: Is It Safe?
Authors: Venskutonis Donatas , Bradulskis Saulius , Adamonis Kestutis , Urbanavicius Linas
Published: September 2007

Background/Aims: Patients often suffer from malnutrition after digestive tract surgery. It leads to a longer recovery and a higher rate of postoperative complications. Early postoperative jejunostomy feeding is a way of tackling this problem. Opinions emerge that feeding via jejunostomy catheter is not the ideal method because of its complications. Our aim was to assess a complication rate of longitudinal Witzel catheter feeding jejunostomy and complications related to the onset of enteral feeding. Methods: A retrospective analysis of case histories of 136 patients operated on for upper digestive tract diseases at our clinic between 1992 and 2004 with catheter feeding jejunostomy as an adjunct. We interviewed our patients by telephone about the jejunostomy-related complications during the 1st postoperative year. Results: We observed two feeding jejunostomy-related complications (1.5%). Complications related to the onset of enteral feeding were observed in 12 cases (26.7%). There was no mortality. No complication of catheter jejunostomy was observed during the 1st postoperative year. Conclusions: A longitudinal Witzel catheter jejunostomy feeding is beneficial after surgery of the upper digestive tract. It is a rather safe procedure, which can be safely started on the day of operation.
Splenic Abscesses Caused by a Reptile-Associated Salmonella Infection
Authors: Berendes T.D. , Keijman J.M.G. , te Velde L.F. , Oostenbroek R.J.
Published: September 2007

Salmonella infections are not very uncommon. The source generally has to be looked for in food. The syndrome concerns mostly gastro-enteritis. We present a 17-year-old girl with sepsis caused by splenic abscesses which was successfully treated with splenectomy and antibiotics. After analysis (blood and surgical specimen samples), she appeared to be infected with Salmonella type Telelkebir, a rare variant that is associated with exotic animal species, mainly reptiles. The same variant was cultivated from the faeces of the reptile pets that were held in the patients’ home. We describe a case with a not often recognized source and an unusual course of Salmonella infection. Exotic pets can be a source of Salmonella infections with a catastrophic course of the disease even in healthy people.
Nutrient-Starved Incubation Conditions Enhance Pyrazinamide Activity against Mycobacterium tuberculosis
Authors: Huang Qiang , Chen Zhi-Fei , Li Yuan-Yuan , Zhang Ying , Ren Yi , Fu Zhijun , Xu Shun-Qing
Published: September 2007

Pyrazinamide (PZA) is an unconventional frontline tuberculosis drug characterized by high in vivo sterilizing activity, but poor in vitroactivity. The study on the mechanism of action of PZA has attracted significant attention because of the peculiarity of PZA and its ability to shorten the tuberculosis chemotherapy. In this study, we examined the effect of nutrient-starved conditions on PZA activity in vitroat acid pH. We also examined the effect of fatty acids, benzoic acid and salicylic acid on PZA activity. The results showed that nutrient-starved conditions lowered the membrane potential of Mycobacterium tuberculosis and enhanced the activity of PZA, with 5- and 10-day starvation conditions resulting in greater enhancement than 3-day starvation. Fatty acids, benzoic acid and salicylic acid enhanced PZA activity in both normal and starved bacilli, especially in starved bacilli. These findings provide further support for the recent model of PZA action and may have implications for developing new drugs that shorten therapy.
Comparison of the Pharmacokinetics of Piperacillin and Sulbactam during Intermittent and Continuous Intravenous Infusion
Authors: Langgartner J. , Lehn N. , Glück T. , Herzig H. , Kees F.
Published: September 2007

Background: The antibacterial effect of piperacillin/sulbactam depends on the time of drug concentration above the minimal inhibitory concentration (MIC). Therefore, continuous infusion (CI) may be a more rational approach than standard intermittent short-term infusion (SI). The study investigated whether CI achieves effective drug concentrations comparable with SI. Methods: Seven intensive care unit patients received either piperacillin/sulbactam as 4/1 g intravenous infusion over 15–20 min every 8 h or as 4/1 g intravenous loading dose (15–20 min) followed by 8/2 g intravenous CI per 24 h. After 2 days, regimes were crossed over. Results: Pharmacokinetic parameters (mean ± SD) for SI piperacillin/sulbactam were: (1) peak serum concentration: piperacillin 231 ± 66 mg/l, sulbactam 53.1 ± 15.0 mg/l; (2) minimum serum concentration: piperacillin 11.5 ± 14.8 mg/l, sulbactam 4.2 ± 3.5 mg/l; (3) clearance: piperacillin 197 ± 72 ml/min (CI 269 ± 123 ml/min), sulbactam 167 ± 61 ml/min (CI 212 ± 109 ml/min); (4) half-life: piperacillin 2.4 ± 1.2 h, sulbactam 3.1 ± 1.6 h. Steady-state concentrations during CI were 25.5 ± 14.5 mg/l for piperacillin and 8.0 ± 3.7 mg/l for sulbactam. Average serum concentrations were comparable in both regimens. Conclusion: A large German survey demonstrated that approximately 89% of Pseudomonas aerugionsa have an MIC ≤16 mg/l and approximately 82% have an MIC ≤8 mg/l. According to this threshold, appropriate anti-bacterial concentrations of piperacillin/sulbactam were achievable with CI. CI dosing has the additional advantage that less drug is necessary. Further prospective studies are warranted to compare the clinical efficacy of CI and SI regimens in bacterial infections.
Anti-Yo-Associated Paraneoplastic Cerebellar Degeneration in a Man with Adenocarcinoma of the Gastroesophageal Junction
Authors: Debes J.D. , Lagarde S.M. , Hulsenboom E. , Sillevis Smitt P.A.E. , ten Kate F.J.W. , Sulter G.A. , van Lanschot J.J.B.
Published: September 2007

Anti-Yo-associated paraneoplastic cerebellar degeneration is a cancer-related syndrome affecting the nervous system. This syndrome occurs almost exclusively in middle-aged women with gynecological cancers and it is rarerly found in patients with other types of cancer or in males. In this report we describe a male patient adenocarcinoma of the gastroesophageal junction and PCD with anti-Yo antibodies. To our knowledge, this is only the third report of PCD with positive anti-Yo antibodies in an esophageal tumor and the first report in a tumor of the gastroesophageal junction.
Electroacupuncture Protects against CCK-Induced Acute Pancreatitis in Rats
Authors: An Hyo-Jin , Lee Ji-Hyun , Lee Hye-Jung , Yang Woong-Mo , Park Seong-Kyu , Hong Seung-Heon , Kim Hyung-Min , Um Jae-Young
Published: September 2007

Objective: Electroacupuncture (EA) has been used to treat myalgia, adiposis and gastroenteropathy in Korea. EA as a complementary and alternative medicine has been accepted worldwide mainly for the treatment acute and chronic pain and inflammation. The aim of this study was to investigate the effects of EA on acute pancreatitis induced by cholecystokinin octapeptide (CCK) in rats. Methods: Animals were divided into four groups: (1) a normal group; (2) a CCK-induced acute pancreatitis group; (3) a CCK-induced acute pancreatitis group treated with 100-Hz EA, and (4) a CCK-induced acute pancreatitis group treated with 2-Hz EA. High-frequency (100-Hz) and low-frequency EA (2-Hz) stimulations were applied to an acupoint equivalent to Zusanli (ST36) in rats, followed by 75 µg/kg CCK subcutaneously three times, after 1, 3 and 5 h. The entire procedure was repeated over 5 days. Repeated CCK treatment resulted in typical laboratory and morphological changes in experimentally induced pancreatitis. Results: EA significantly decreased the pancreatic weight/body weight ratio in CCK-induced acute pancreatitis, increased the pancreatic levels of HSP60 and HSP72, and decreased the β-amylase and lipase levels associated with CCK-induced acute pancreatitis. Furthermore, the release of ACTH was increased in the blood serum of the EA-treated group. Conclusion: EA may have protective effects against CCK-induced acute pancreatitis through the release of ACTH.
A Dose Escalation Study of Biweekly Oral Vinorelbine and Gemcitabine in Patients with Solid Tumors
Authors: Karampeazis A. , Vamvakas L. , Agelaki S. , Kentepozidis N. , Papadimitraki E. , Gioulbasanis I. , Vardakis N. , Ignatiadis M. , Mavroudis D. , Georgoulias V.
Published: September 2007

Purpose: To determine the maximum tolerated doses (MTDs) and the dose-limiting toxicities of a biweekly administration of oral vinorelbine and gemcitabine in patients with advanced solid tumors. Patients and Methods: Twenty-eight patients with advanced stage solid tumors were enrolled, and 12 (42.9%) of them were chemotherapy naive. Escalating doses of vinorelbine (50–70 mg/m2 per os) and gemcitabine (800–1,000 mg/m2 as a 30-min intravenous infusion) were administered on days 1 and 15 in 4-week cycles. Results: MTDs were reached at 70 mg/m2 p.o. for vinorelbine and 900 mg/m2 for gemcitabine. Grade 4 neutropenia, febrile neutropenia, grade 4 nausea/vomiting and treatment delay due to grade 3 neutropenia were the dose-limiting events during the first cycle of chemotherapy. A total of 94 chemotherapy cycles were administered with only one episode of febrile neutropenia and no toxic deaths. Severe (grade 3–4) neutropenia occurred in 10% of cycles while non-hematological toxicity was mild with grade 2–3 asthenia occurring in 17 (18%) cycles. Objective responses were achieved in patients with prostate and non-small cell lung cancer. Conclusions: The combination of biweekly oral vinorelbine (70 mg/m2) and gemcitabine (900 mg/m2) is a well-tolerated regimen with promising results in patients with advanced solid tumors.
Nonhematological Benefits of Iron
Authors: Agarwal Rajiv
Published: September 2007

Iron deficiency anemia is common in people with chronic kidney disease (CKD) and its importance in supporting erythropoiesis is unquestioned especially in those patients treated with erythropoietin. Clinical symptomatology such as fatigability, cold intolerance, failure to concentrate and poor effort intolerance is often attributed to anemia or uremia. That iron deficiency, per se, can cause these symptoms is poorly recognized. Clinical and animal studies that support the benefits of iron supplementation, independent of increasing hemoglobin, such as those on immune function, physical performance, thermoregulation, cognition, and restless leg syndrome and aluminum absorption is the subject of this narrative review.
Effect of Distal Embolization on Myocardial Perfusion Reserve After Percutaneous Coronary Intervention
Authors: Selvanayagam Joseph B. , Cheng Adrian S.H. , Jerosch-Herold Michael , Rahimi Kazem , Porto Italo , van Gaal William , Channon Keith M. , Neubauer Stefan , Banning Adrian P.
Published: September 2007

Background—

Studies have shown that a subset of patients demonstrate persistent impairment in microcirculatory function after percutaneous coronary intervention (PCI). Distal embolization of plaque contents has been postulated as the main mechanism for this. We sought to investigate this further by evaluating PCI-induced changes in myocardial perfusion reserve index (MPRI) over time in segments with “distal-type” procedure-related myonecrosis using high-resolution quantitative cardiovascular magnetic resonance imaging.

Methods and Results—

Forty patients undergoing PCI were studied with pre-PCI and 24-hour post-PCI delayed-enhancement magnetic resonance imaging and first-pass perfusion magnetic resonance imaging at rest and stress. Twenty patients underwent a third magnetic resonance imaging scan at 6 months. For perfusion imaging, 3 short-axis images were acquired during every heartbeat with a T1-weighted turboFLASH sequence. MPRI was calculated as the ratio of hyperemic to resting myocardial blood flow and subdivided according to the presence and location of new delayed hyperenhancement. Twenty-one patients demonstrated new distal hyperenhancement after PCI. Mean MPRI in revascularized myocardial segments not demonstrating new HE was significantly increased after the procedure (2.06 [95% CI, 1.99 to 2.13] before PCI and 2.52 [95% CI, 2.42 to 2.62] after PCI;
P
<0.001). In contrast, MPRI in segments with distal hyperenhancement was reduced after PCI (2.16 [95% CI, 1.95 to 2.37] before PCI; 2.00 [95% CI, 1.82 to 2.19] after PCI; mixed-model
z
=−4.82;
P
<0.001). Changes in mean MPRI 24 hours after PCI in segments upstream to new injury were not significantly different compared with perfusion changes in remote myocardium (
z
=−0.68;
P
=0.50). At 6 months after the procedure, mean MPRI in segments with new injury improved significantly compared with MPRI measured in these segments at 24 hours after PCI.

Conclusions—

MPRI is reduced in myocardial segments that demonstrate new distal irreversible injury at 24 hours after PCI. These reductions are confined to the segments with injury and do not affect the entire supply territory of the culprit vessel.
Left Ventricular Resynchronization Is Mandatory for Response to Cardiac Resynchronization Therapy
Authors: Bleeker Gabe B. , Mollema Sjoerd A. , Holman Eduard R. , Van De Veire Nico , Ypenburg Claudia , Boersma Eric , van der Wall Ernst E. , Schalij Martin J. , Bax Jeroen J.
Published: September 2007

Background—

Recent studies have demonstrated that a positive response to cardiac resynchronization therapy (CRT) is related to the presence of preimplantation left ventricular (LV) dyssynchrony. The time course and the extent of LV resynchronization after CRT implantation and their relationship to response are currently unknown.

Methods and Results—

One hundred consecutive patients scheduled for implantation of a CRT device were prospectively included if they met the following criteria: New York Heart Association class III to IV, LV ejection fraction ≤35%, QRS duration >120 ms, and LV dyssynchrony (≥65 ms) on color-coded tissue Doppler imaging. Immediately after CRT implantation, LV dyssynchrony was reduced from 114±36 to 40±33 ms (
P
<0.001), which persisted at the 6-month follow-up (35±31 ms;
P
<0.001 versus baseline;
P
=0.14 versus immediately after implantation). At the 6-month follow-up, 85% of patients were classified as responders to CRT (defined as >10% reduction in LV end-systolic volume). Immediately after implantation, the responders to CRT demonstrated a significant reduction in LV dyssynchrony from 115±37 to 32±23 ms (
P
<0.001). The nonresponders, however, did not show a significant reduction in LV dyssynchrony (106±29 versus 79±44 ms;
P
=0.08). If the extent of acute LV resynchronization was <20%, response to CRT at the 6-month follow-up was never observed. Conversely, 93% of patients with LV resynchronization ≥20% responded to CRT.

Conclusions—

LV resynchronization after CRT is an acute phenomenon and predicts response to CRT at 6-month follow-up in patients with echocardiographic evidence of LV dyssynchrony at baseline.
Cardioprotection Afforded by Inducible Nitric Oxide Synthase Gene Therapy Is Mediated by Cyclooxygenase-2 via a Nuclear Factor-κB–Dependent Pathway
Authors: Li Qianhong , Guo Yiru , Tan Wei , Ou Qinghui , Wu Wen-Jian , Sturza Diana , Dawn Buddhadeb , Hunt Greg , Cui Chuanjue , Bolli Roberto
Published: September 2007

Background—

Gene therapy with inducible nitric oxide synthase (iNOS) markedly reduces myocardial infarct size; this effect is associated with cyclooxygenase-2 (COX-2) upregulation and is ablated by COX-2 inhibitors. However, pharmacological inhibitors are limited by relative lack of specificity; furthermore, the mechanism whereby
iNOS
gene therapy upregulates COX-2 remains unknown. Accordingly, we used genetically engineered mice to test the hypothesis that the cardioprotection afforded by
iNOS
gene transfer is mediated by COX-2 upregulation via a nuclear factor (NF)-κB–dependent pathway.

Methods and Results—

Mice received an intramyocardial injection of Av3/LacZ (LacZ group) or Av3/iNOS (iNOS group); 3 days later, myocardial infarction was produced by a 30-minute coronary occlusion followed by 4 hours of reperfusion. Among Av3/LacZ-treated mice, infarct size was similar in
COX-2
−/−
and wild-type groups.
iNOS
gene transfer (confirmed by iNOS immunoblotting and activity assays) markedly reduced infarct size in wild-type mice but failed to do so in
COX-2
−/−
mice. In transgenic mice with cardiac-specific expression of a dominant-negative mutant of IκBα (IκBα
S32A,S36A
), the upregulation of phosphorylated IκBα, activation of NF-κB, and cardiac COX-2 protein expression 3 days after
iNOS
gene therapy were abrogated, which was associated with the abolishment of the cardioprotective effects afforded by
iNOS
gene therapy.

Conclusions—

These data provide strong genetic evidence that COX-2 is an obligatory downstream effector of iNOS-dependent cardioprotection and that NF-κB is a critical link between iNOS and COX-2. Thus, iNOS imparts its protective effects, at least in part, by recruiting NF-κB, leading to COX-2 upregulation. However, COX-2 does not play an important cardioprotective role under basal conditions (when iNOS is not upregulated).
Clinical Characteristics of Dialysis Patients With Acute Myocardial Infarction in the United States
Authors: Herzog Charles A. , Littrell Kathee , Arko Cheryl , Frederick Paul D. , Blaney Martha
Published: September 2007

Background—

Acute myocardial infarction (AMI) is catastrophic for dialysis patients. This study set out to determine the clinical characteristics of dialysis patients hospitalized for AMI in the United States.

Methods and Results—

This retrospective cohort study used data from the US Renal Data System (USRDS) database (n=1 285 177) and the third National Registry of Myocardial Infarction (NRMI 3) (n=537 444). AMI hospitalizations from April 1, 1998, through June 30, 2000, were identified using
International Classification of Diseases
, 9th edition, clinical modification, codes 410, 410.x, 410.x0, and 410.x1. The 9418 unique dialysis patients identified with AMI hospitalizations in the USRDS database were cross-matched with the NRMI registry, creating a cohort for analysis that consisted of 3049 matching patients. Clinical characteristics of dialysis and nondialysis (n=534 395) AMI patients were compared by use of the χ
2
test. Of clinical significance, 44.8% of dialysis patients were diagnosed as not having acute coronary syndrome on admission, versus 21.2% of nondialysis patients; 44.4% presented with chest pain, versus 68.3% of nondialysis patients; and 19.1% had ST elevation, versus 35.9% of nondialysis patients. Cardiac arrest was twice as frequent for dialysis patients (11.0% versus 5.0%), and in-hospital death was nearly so (21.3% versus 11.7%). In a logistic regression model, the odds ratio for in-hospital death for dialysis versus nondialysis patients was 1.498 (95% CI, 1.340 to 1.674).

Conclusions—

Dialysis patients hospitalized for AMI differ strikingly from nondialysis patients, which possibly explains their poor outcomes. Intensive efforts for early, accurate recognition of AMI in dialysis patients are warranted.
Gender-Specific Associations of Short Sleep Duration With Prevalent and Incident Hypertension
Authors: Cappuccio Francesco P. , Stranges Saverio , Kandala Ngianga-Bakwin , Miller Michelle A. , Taggart Frances M. , Kumari Meena , Ferrie Jane E. , Shipley Martin J. , Brunner Eric J. , Marmot Michael G.
Published: September 2007

Sleep deprivation (≤5 hour per night) was associated with a higher risk of hypertension in middle-aged American adults but not among older individuals. However, the outcome was based on self-reported diagnosis of incident hypertension, and no gender-specific analyses were included. We examined cross-sectional and prospective associations of sleep duration with prevalent and incident hypertension in a cohort of 10 308 British civil servants aged 35 to 55 years at baseline (phase 1: 1985–1988). Data were gathered from phase 5 (1997–1999) and phase 7 (2003–2004). Sleep duration and other covariates were assessed at phase 5. At both examinations, hypertension was defined as blood pressure ≥140/90 mm Hg or regular use of antihypertensive medications. In cross-sectional analyses at phase 5 (n=5766), short duration of sleep (≤5 hour per night) was associated with higher risk of hypertension compared with the group sleeping 7 hours, among women (odds ratio: 2.01; 95% CI: 1.13 to 3.58), independent of confounders, with an inverse linear trend across decreasing hours of sleep (
P
=0.003). No association was detected in men. In prospective analyses (mean follow-up: 5 years), the cumulative incidence of hypertension was 20.0% (n=740) among 3691 normotensive individuals at phase 5. In women, short duration of sleep was associated with a higher risk of hypertension in a reduced model (age and employment) (6 hours per night: odds ratio: 1.56 [95% CI: 1.07 to 2.27]; ≤5 hour per night: odds ratio: 1.94 [95% CI: 1.08 to 3.50] versus 7 hours). The associations were attenuated after accounting for cardiovascular risk factors and psychiatric comorbidities (odds ratio: 1.42 [95% CI: 0.94 to 2.16]; odds ratio: 1.31 [95% CI: 0.65 to 2.63], respectively). Sleep deprivation may produce detrimental cardiovascular effects among women.
Policy Positions, Issue Importance, and Party Competition in New Democracies
Authors: Tavits Margit
Published: September 2007

This article examines the dynamics of vote redistribution after new party entry in the context of East European democracies. Contrary to the dominant institutional and sociological approaches, the author focuses on the (strategic) policy choices of the new contestants. The author argues that a new party's choice about where to place itself in relation to existing parties and which issues to emphasize can determine its electoral success or failure. Aggregate and individual-level analyses confirm this argument. The findings underline the importance of policy-based party competition in the region. As a broader theoretical contribution, the study underscores the relevance of issue importance, and not just party issue positions, in political competition.
Gardening Activities, Education, and Self-Esteem
Authors: Hoffman August John , Morales Knight Luis F. , Wallach Julie
Published: September 2007

Numerous articles have been written about the impact of community-based work and self-esteem, self-efficacy, and gardening in an educational environment. Empirical data suggest that when students have become involved in a group effort designed to improve a school, community, or society, a sense of interdependency and loyalty to that institution develops. The purpose of the current article is to illustrate the effects of a gardening program on improving gardening self-esteem and reducing ethnocentrism among community college students. An additional goal of the study was to illustrate how the improvements in self-esteem among students also resulted in increased community involvement and awareness. Results of the study suggest that when a learning institution provides mechanisms for students to contribute to the overall quality of the institution (such as a campus gardening program), a sense of interdependency and positive self-empowerment develops among faculty and students.
Lost and Turned Out
Authors: Brown Tara M.
Published: September 2007

This study examines the experiences of 37 students who were suspended or expelled from school and were attending an urban public alternative high school in the northeast. The analysis specifically focuses on the loss of classroom instruction time and its implications for academic achievement and on the socioemotional experiences of students excluded from the educational mainstream. This study draws on survey data and the author's own experience as a teacher at the school to show how school exclusion was related to students' academic and social and emotional well-being. Implications for further research on this topic are explored.
Conceptualizing Special Education Services in Small Learning Communities
Authors: Dukes Charles , Lamar-Dukes Pamela
Published: September 2007

The ills of urban schools are well documented. The challenges of recruiting and retaining quality teachers, student mobility, poor conditions of school facilitates, and lack of parent involvement are only a few of the issues related to urban schools. Large comprehensive high schools are a staple of many urban school districts. This model of educating a large number of students in one school has come into question. The reduction in size of schools, especially large comprehensive high schools is now the focus of many school reform efforts. Lost in this discussion is the consideration of special education services and how special education services can be effectively integrated into any small school or small learning community restructuring efforts. A possible model of how special education services can be integrated into high schools restructured into small learning communities is presented, including considerations of benefits for students with and without disabilities.
The Designated Hitter Rule and Team Defensive Strategy in Japan's Professional Baseball Leagues
Authors: Kawaura Akihiko , La Croix Sumner J.
Published: September 2007

Economists have debated whether and why the designated hitter (DH) rule in North American Major League Baseball led to an increase in hit batsmen. We use data from Japan's professional baseball leagues to reexamine this question. Our empirical analyses of hit batsmen for batters as well as by pitchers reveal that the DH rule resulted in increases in hit batsmen even after effects of team batting performance and pitcher quality are controlled for. We argue that the DH rule prompted changes in managerial defensive strategies, in which pitchers of poorly performing teams are instructed to engage in aggressive pitching.
Revenue Sharing and Owner Profits in Professional Team Sports
Authors: Kesenne Stefan
Published: September 2007

In the sports economics literature, little attention has been paid to the impact of revenue sharing on club owners' profits. In particular, it is unclear how the profits of the large-budget clubs are affected. In this article, the relationship between one specific revenue-sharing arrangement and owner profits is investigated for clubs in a profit-maximization league using two different models. In a Walrasian equilibrium model, revenue sharing will lower profits, whatever the value of the share parameter, if the profits of a large-budget club are higher than the average club budget in the league. In a noncooperative Nash equilibrium model, the impact turns out to be theoretically indeterminate.
Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPARγ cross talk with NF-κB and C/EBPβ
Authors: Wang Li Hua , Yang Xiao Yi , Zhang Xiaohu , Farrar William L.
Published: September 2007

Binding of multiple myeloma (MM) cells to bone marrow stromal cells (BMSCs) triggers expression of adhesive molecules and secretion of interleukin-6 (IL-6), promoting MM cell growth, survival, drug resistance, and migration, which highlights the possibility of developing and validating novel anti-MM therapeutic strategies targeting MM cells–host BMSC interactions and their sequelae. Recently, we have found that expression of the peroxisome proliferator-activated receptor γ (PPARγ) and its ligands can potently inhibit IL-6–regulated MM cell growth. Here we demonstrate that PPARγ agonists 15-d-PGJ2 and troglitazone significantly suppress cell-cell adhesive events, including expression of adhesion molecules and IL-6 secretion from BMSCs triggered by adhesion of MM cells, as well as overcome drug resistance by a PPARγ-dependent mechanism. The synthetic and natural PPARγ agonists have diverging and overlapping mechanisms blocking transactivation of transcription factors NF-κB and 5′-CCAAT/enhancer–binding protein β (C/EBPβ). Both 15-d-PGJ2 and troglitazone blocked C/EBPβ transcriptional activity by forming PPARγ complexes with C/EBPβ. 15-d-PGJ2 and troglitazone also blocked NF-κB activation by recruiting the coactivator PGC-1 from p65/p50 complexes. In addition, 15-d-PGJ2 had a non–PPARγ-dependent effect by inactivation of phosphorylation of IKK and IκB. These studies provide the framework for PPARγ-based pharmacological strategies targeting adhesive interactions of MM cells with the bone marrow microenvironment.
Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors
Authors: Cortes Jorge , Jabbour Elias , Kantarjian Hagop , Yin C. Cameron , Shan Jianqin , O'Brien Susan , Garcia-Manero Guillermo , Giles Francis , Breeden Megan , Reeves Nubia , Wierda William G. , Jones Dan
Published: September 2007

Dasatinib and nilotinib are potent tyrosine kinase inhibitors (TKIs) with activity against many imatinib-resistant chronic myeloid leukemia (CML) clones with BCR-ABL kinase domain (KD) mutations, except T315I. We assessed for changes in the BCR-ABL KD mutation status in 112 patients with persistent CML who received a second-generation TKI after imatinib failure. Sixty-seven different KD mutations were detected before the start of therapy with a second TKI, with T315I seen in 15%. Equal numbers of patients received nilotinib or dasatinib following imatinib, and 18 received 3 TKIs. Response rates were similar for patients with and without mutations, regardless of mutation site except for T315I. Overall, 29 patients (26%) developed new KD mutations after therapy with a second (n = 24) or third (n = 5) TKI, but only 4 (4%) developed T315I. In 73% of cases, the KD mutations that persisted or developed following switch to new TKI were at sites also found in prior in vitro TKI mutagenesis assays. Although there is only a mild increase in mutation frequency with sequential TKI treatment, novel mutations do occur and mutation regression/acquisition/persistence generally reflects the in vitro differential sensitivity predicted for each TKI. In this study, there was no marked increase in development of T315I.
Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8)
Authors: Guzman Monica L. , Li Xiaojie , Corbett Cheryl A. , Rossi Randall M. , Bushnell Timothy , Liesveld Jane L. , Hébert Josée , Young Fay , Jordan Craig T.
Published: September 2007

Leukemia is thought to arise from malignant stem cells, which have been described for acute and chronic myeloid leukemia (AML and CML) and for acute lymphoblastic leukemia (ALL). Leukemia stem cells (LSCs) are relatively resistant to current chemotherapy and likely contribute to disease relapse and progression. Consequently, the identification of drugs that can efficiently eradicate LSCs is an important priority. In the present study, we investigated the antileukemia activity of the compound TDZD-8. Analysis of primary AML, blast crisis CML (bcCML), ALL, and chronic lymphoblastic leukemia (CLL) specimens showed rapid induction of cell death upon treatment with TDZD-8. In addition, for myeloid leukemias, cytotoxicity was observed for phenotypically primitive cells, in vitro colony-forming progenitors, and LSCs as defined by xenotransplantation assays. In contrast, no significant toxicity was observed for normal hematopoietic stem and progenitor cells. Notably, cell death was frequently evident within 2 hours or less of TDZD-8 exposure. Cellular and molecular studies indicate that the mechanism by which TDZD-8 induces cell death involves rapid loss of membrane integrity, depletion of free thiols, and inhibition of both the PKC and FLT3 signaling pathways. We conclude that TDZD-8 uses a unique and previously unknown mechanism to rapidly target leukemia cells, including malignant stem and progenitor populations.