bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phase I Trial of Twice-Weekly 17-Allylamino-Demethoxy-Geldanamycin in Patients with Advanced Cancer
Authors: Nowakowski Grzegorz S. , McCollum Andrea K. , Ames Matthew M. , Mandrekar Sumithra J. , Reid Joel M. , Adjei Alex A. , Toft David O. , Safgren Stephanie L. , Erlichman Charles
Published: October 2006

Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of 17-allylamino-demethoxy-geldanamycin (17-AAG) administered on days 1, 4, 8, and 11 every 21 days and to examine the effect of 17-AAG on the levels of chaperone and client proteins.

Experimental Design: A phase I dose escalating trial in patients with advanced solid tumors was done. Toxicity and tumor responses were evaluated by standard criteria. Pharmacokinetics were done and level of target proteins was measured at various points during cycle one.

Results: Thirteen patients were enrolled in the study. MTD was defined as 220 mg/m2. Dose-limiting toxicities were as follows: dehydration, diarrhea, hyperglycemia, and liver toxicity. At the MTD, the mean clearance of 17-AAG was 18.7 L/h/m2. There was a significant decrease in integrin-linked kinase at 6 hours after infusion on day 1 but not at 25 hours in peripheral blood mononuclear cells. Treatment with 17-AAG on day 1 significantly increased pretreatment levels of heat shock protein (HSP) 70 on day 4, which is consistent with the induction of a stress response. In vitro induction of a stress response and up-regulation of HSP70 resulted in an increased resistance to HSP90-targeted therapy in A549 cells.

Conclusions: The MTD of 17-AAG on a twice-weekly schedule was 220 mg/m2. Treatment at this dose level resulted in significant changes of target proteins and also resulted in a prolonged increase in HSP70. This raises the possibility that HSP70 induction as part of the stress response may contribute to resistance to 17-AAG.
Piroxicam and Cisplatin in a Mouse Model of Peritoneal Mesothelioma
Authors: Spugnini Enrico P. , Cardillo Irene , Verdina Alessandra , Crispi Stefania , Saviozzi Silvia , Calogero Raffaele , Nebbioso Angela , Altucci Lucia , Cortese Giancarlo , Galati Rossella , Chien Jeremy , Shridhar Viji , Vincenzi Bruno , Citro Gennaro , Cognetti Francesco , Sacchi Ada , Baldi Alfonso
Published: October 2006

Purpose: The aim of the present study was to evaluate the effects of piroxicam, a widely used nonsteroidal anti-inflammatory drug, alone and in combination with cisplatin (CDDP), on cell growth of mesothelioma cells.

Experimental Design: Cell proliferation, cell cycle analysis, and microarray technology were done on MSTO-211H and NCI-H2452 cells treated with piroxicam. Moreover, the effects of piroxicam and CDDP on tumor growth and survival of mouse xenograft models of mesothelioma were determined.

Results: Piroxicam treatment of MSTO-211H and NCI-H2452 cells resulted in a significant inhibition of proliferation. Cell cycle analysis revealed that there was an increase in the rate of apoptosis in MSTO-211H cells and an increase in the cells accumulating in G2-M in NCI-H2452. Moreover, a marked tumor growth inhibition and an extended survival of mice treated with a combination of piroxicam and CDDP in MSTO-211H cell–induced peritoneal mesotheliomas was observed. Last, GeneChip array analysis of MSTO-211H mesothelioma cell line revealed that piroxicam treatment caused up-regulation of metabolic pathway–associated genes and down-regulation of genes related to RNA processing apparatus. Of note, epidermal growth factor receptor, one of the new biological targets of chemotherapy for mesothelioma, was down-regulated and HtrA1, a serine protease recently shown to be an endogenous mediator of CDDP cytotoxicity, was up-regulated following piroxicam treatment both in vitro and in vivo.

Conclusion: These data suggest that piroxicam sensitizes mesothelioma cells to CDDP-induced cytotoxicity by modulating the expression of several target genes. Therefore, piroxicam in combination with CDDP might potentially be useful in the treatment of patients with mesothelioma.
A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer
Authors: Kershaw Michael H. , Westwood Jennifer A. , Parker Linda L. , Wang Gang , Eshhar Zelig , Mavroukakis Sharon A. , White Donald E. , Wunderlich John R. , Canevari Silvana , Rogers-Freezer Linda , Chen Clara C. , Yang James C. , Rosenberg Steven A. , Hwu Patrick
Published: October 2006

Purpose: A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the treatment of metastatic ovarian cancer.

Experimental Design: T cells with reactivity against the ovarian cancer–associated antigen α-folate receptor (FR) were generated by genetic modification of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of the Fc receptor γ chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1 received a dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear cells.

Results: Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2 administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects with grade 1 to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking 111In-labeled adoptively transferred T cells in cohort 1 revealed a lack of specific localization of T cells to tumor except in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable 1 month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR+ tumor cells.

Conclusions: Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to document the use of genetically redirected T cells for the treatment of ovarian cancer.
Met Receptor Signaling: A Key Effector in Esophageal Adenocarcinoma
Authors: Anderson Mark R. , Harrison Rebecca , Atherfold Paul A. , Campbell Moray J. , Darnton S. Jane , Obszynska Jolanta , Jankowski Janusz A.Z
Published: October 2006

Purpose: The incidence of esophageal adenocarcinoma is rising, and survival rates remain poor. The hepatocyte growth factor (HGF) receptor Met has been detected in esophageal cancer. The perturbation of cadherin/catenin complexes has also been shown. We sought to investigate a link among Met expression, cadherin/catenin biology, and cell growth. We assessed the prognostic significance of Met expression in esophageal adenocarcinoma.

Experimental Design: Met and HGF expression in esophageal tissues were assessed using immunohistochemistry and ELISA. Met-positive cell lines (OE33 and SEG1) and a Met-negative cell line (TE7) were incubated with HGF. Real-time reverse transcription-PCR and Western blotting were used to assess levels of E-cadherin expression. Nuclear TCF/β-catenin signaling was assessed following reporter construct transfection. Agar colony formation was used to assess anchorage-independent growth. A panel of 72 resected esophageal adenocarcinomas were assessed for Met expression by immunohistochemistry and correlated to survival data.

Results: An increased expression of Met was seen along the metaplasia- adenocarcinoma sequence. Met-positive cells showed reductions in E-cadherin mRNA (37% and 69%) and protein expression following stimulation with HGF (P < 0.01). OE33 and SEG-1 showed up to a 2-fold increase in the levels of β-catenin nuclear signaling (P < 0.01). TE7 only responded when transfected to express Met; E-cadherin expression decreased by 64% (P < 0.01). HGF stimulation led to increased agar colony formation (P < 0.01). Patients with Met-positive tumors showed lower 6-month survival rates after surgical resection than those with Met-negative tumors (P < 0.05).

Conclusions: Met activation induces changes consistent with early invasion, such as down-regulation of E-cadherin, increased nuclear TCF/β-catenin signaling, and anchorage-independent growth. This is supported by ex vivo data associating Met with reduced short-term survival. Inhibitors of Met may be effective treatment for esophageal adenocarcinoma.
Randomized Phase II Study of Interleukin-12 in Combination with Rituximab in Previously Treated Non-Hodgkin's Lymphoma Patients
Authors: Ansell Stephen M. , Geyer Susan M. , Maurer Matthew J. , Kurtin Paul J. , Micallef Ivana N.M. , Stella Philip , Etzell Paul , Novak Anne J. , Erlichman Charles , Witzig Thomas E.
Published: October 2006

Purpose: Rituximab is a chimeric antibody that induces B-cell apoptosis and recruits immune effector cells to mediate cell lysis. Interleukin-12 (IL-12) facilitates cytolytic responses by T cells and natural killer cells. This phase II study was done to determine the efficacy and toxicity of IL-12 in combination with rituximab in patients with B-cell non-Hodgkin's lymphoma (NHL).

Experimental Design: Fifty-eight patients with histologically confirmed relapsed B-cell NHL were randomized to receive concurrent treatment with rituximab and IL-12 (arm A) or rituximab with subsequent treatment with IL-12 after documented nonresponse or progression after rituximab (arm B). Treatment consisted of 375 mg/m2 rituximab on days 1, 8, 15, and 22 and 300 ng/kg IL-12 given s.c. twice weekly starting on day 2 for arm A or upon progression for arm B.

Results: The overall response rate was 37% (11 of 30) in arm A and 52% (13 of 25) in arm B. All of the responses seen in arm B occurred while patients received rituximab, and no responses occurred during treatment with subsequent IL-12. The median duration of response was 16 months for arm A and 12 months for arm B. Biopsy specimens were serially obtained in a subset of patients and showed that changes in gene expression were different when cells from the peripheral blood were compared with cells from lymph node biopsies.

Conclusions: The concomitant use of IL-12 and rituximab had modest disease activity in patients with B-cell NHL, but the sequential administration of IL-12 after rituximab did not result in additional clinical responses.
Biological Role of Estrogen Receptor β in Salivary Gland Adenocarcinoma Cells
Authors: Ohshiro Kazufumi , Rayala Suresh K. , Williams Michelle D. , Kumar Rakesh , El-Naggar Adel K.
Published: October 2006

Purpose: This study is intended to investigate the biological role of estrogen receptor (ER) nongenomic signaling in salivary gland adenocarcinoma cells that predominantly express ERβ.

Experimental Design: Salivary gland adenocarcinoma cell lines HSG and HSY were used to study the effect of diarylpropionitrile and estrogen on the nongenomic signaling of ERβ, cytoskeletal remodeling, and cell motility.

Results: We found that diarylpropionitrile and estrogen triggered rapid activation of the extracellular signal-regulated kinase 1/2 (ERK), Src, and focal adhesion kinase signaling pathways. Estrogen stimulation also induced long cytoplasmic extensions, filopodia formation, and abnormal outgrowths in both HSG and HSY cells. We further observed that ligand-induced migration of these cells was blocked by the pure antiestrogen ICI 182780 and the mitogen-activated protein/ERK kinase inhibitor PD98059, indicating that estrogen-induced cell migration is mediated by the activation of ERβ nongenomic signaling.

Conclusion: These results clearly showed that ERβ nongenomic signaling is active in salivary gland cells and has a biological role in migration, presumably via the stimulation of ERK1/2. In future, the findings of this study might have clinical importance as several ERβ-selective agonists are currently being available, and these could potentially be used for therapeutic targeting of ERβ-positive salivary tumors.
Grape Seed Extract Inhibits In vitro and In vivo Growth of Human Colorectal Carcinoma Cells
Authors: Kaur Manjinder , Singh Rana P. , Gu Mallikarjuna , Agarwal Rajesh , Agarwal Chapla
Published: October 2006

Purpose: Accumulating evidences suggest the beneficial effects of fruit-and-vegetable consumption in lowering the risk of various cancers, including colorectal cancer. Herein, we investigated the in vitro and in vivo anticancer effects and associated mechanisms of grape seed extract (GSE), a rich source of proanthocyanidins, against colorectal cancer.

Experimental Design: Effects of GSE were examined on human colorectal cancer HT29 and LoVo cells in culture for proliferation, cell cycle progression, and apoptosis. The in vivo effect of oral GSE was examined on HT29 tumor xenograft growth in athymic nude mice. Xenografts were analyzed by immunohistochemistry for proliferation and apoptosis. The molecular changes associated with the biological effects of GSE were analyzed by Western blot analysis.

Results: GSE (25-100 μg/mL) causes a significant dose- and time-dependent inhibition of cell growth with concomitant increase in cell death. GSE induced G1 phase cell cycle arrest along with a marked increase in Cip1/p21 protein level and a decrease in G1 phase–associated cyclins and cyclin-dependent kinases. GSE-induced cell death was apoptotic and accompanied by caspase-3 activation. GSE feeding to mice at 200 mg/kg dose showed time-dependent inhibition of tumor growth without any toxicity and accounted for 44% decrease in tumor volume per mouse after 8 weeks of treatment. GSE inhibited cell proliferation but increased apoptotic cell death in tumors. GSE-treated tumors also showed enhanced Cip1/p21 protein levels and poly(ADP-ribose) polymerase cleavage.

Conclusions: GSE may be an effective chemopreventive agent against colorectal cancer, and that growth inhibitory and apoptotic effects of GSE against colorectal cancer could be mediated via an up-regulation of Cip1/p21.
Local Renin Angiotensin Expression Regulates Human Mesenchymal Stem Cell Differentiation to Adipocytes
Authors: Matsushita Kenichi , Wu Yaojiong , Okamoto Yoshihisa , Pratt Richard E. , Dzau Victor J.
Published: October 2006

Clinical and experimental evidence suggest that the renin–angiotensin system (RAS) plays a role in metabolic syndrome. Adipogenesis is suggested to modulate obesity and obesity-related consequences, such as metabolic syndrome. Although mesenchymal stem cells (MSCs) are a major source of adipocyte generation, the influence of RAS on MSC differentiation to adipocyte is unknown. We evaluated the expression of endogenous RAS in human MSCs during its differentiation to adipocytes and studied the effects of angiotensin II (Ang II), Ang II type 1 receptor blocker Valsartan, and type 2 (AT
2
) receptor blocker PD123319. Our data showed that differentiation was associated with an increase in cellular renin and AT
2
receptor expression and a concomitant decrease in angiotensinogen and angiotensin-converting enzyme expression. The net effect is an increase in endogenous cellular angiotensin II production. Incubation with Ang II (exogenous) inhibited adipogenesis. Combined treatment of exogenous Ang II and Valsartan further inhibited adipogenesis, whereas combined treatment of Ang II and PD123319 completely abolished the inhibition of adipogenesis, suggesting an important role for the AT
2
receptor. Blockade of endogenous angiotensin II effect by incubation with Valsartan alone inhibited adipogenesis, whereas PD123319 alone promoted adipogenesis, confirming the data using exogenous Ang II. The combination of Valsartan and PD123319 had no net effect. Our data demonstrate an important role of the expression of the local RAS in the regulation of human MSC differentiation to adipocytes. Elucidation of the molecular mechanism should provide important insight into the pathophysiology of the metabolic syndrome and the development of future therapeutics.
Low Carbohydrate/High-Fat Diet Attenuates Cardiac Hypertrophy, Remodeling, and Altered Gene Expression in Hypertension
Authors: Okere Isidore C. , Young Martin E. , McElfresh Tracy A. , Chess David J. , Sharov Victor G. , Sabbah Hani N. , Hoit Brian D. , Ernsberger Paul , Chandler Margaret P. , Stanley William C.
Published: October 2006

The effects of dietary fat intake on the development of left ventricular hypertrophy and accompanying structural and molecular remodeling in response to hypertension are not understood. The present study compared the effects of a high-fat versus a low-fat diet on development of left ventricular hypertrophy, remodeling, contractile dysfunction, and induction of molecular markers of hypertrophy (ie, expression of mRNA for atrial natriuretic factor and myosin heavy chain β). Dahl salt-sensitive rats were fed either a low-fat (10% of total energy from fat) or a high-fat (60% of total energy from fat) diet on either low-salt or high-salt (6% NaCl) chow for 12 weeks. Hearts were analyzed for mRNA markers of ventricular remodeling and activities of the mitochondrial enzymes citrate synthase and medium chain acyl-coenzyme A dehydrogenase. Similar levels of hypertension were achieved with high-salt feeding in both diet groups (systolic pressure of ≈190 mm Hg). In hypertensive rats fed low-fat chow, left ventricular mass, myocyte cross-sectional area, and end-diastolic volume were increased, and ejection fraction was decreased; however, these effects were not observed with the high-fat diet. Hypertensive animals on low-fat chow had increased atrial natriuretic factor mRNA, myosin heavy chain isoform switching (α to β), and decreased activity of citrate synthase and medium chain acyl-coenzyme A dehydrogenase, which were all attenuated by high-fat feeding. In conclusion, increased dietary lipid intake can reduce cardiac growth, left ventricular remodeling, contractile dysfunction, and alterations in gene expression in response to hypertension.
Abnormal Pressure Passive Dilatation of Cerebral Arterioles in the Elderly With Isolated Systolic Hypertension
Authors: Castellani Sergio , Bacci Marzia , Ungar Andrea , Prati Patrizio , Di Serio Claudia , Geppetti Pierangelo , Masotti Giulio , Neri Serneri Gian Gastone , Gensini Gian Franco
Published: October 2006

The aim of this study was to investigate the cerebrovascular adaptability to 2 sequential pressor stimuli in elderly patients with isolated systolic hypertension. Ten healthy elderly normotensive subjects (68 to 82 years), 10 elderly subjects with isolated systolic hypertension (63 to 82 years), and 10 young normotensive subjects (24 to 40 years) took part in the study. A pressor reaction, using sequential cold pressor and handgrip stimulation, was induced. The cerebrovascular response to the pressor stimulation was measured by transcranial Doppler determination of the mean flow velocity in the middle cerebral arteries. In all of the subjects, blood pressure increased during handgrip (+12 mm Hg,
P
<0.001 in the young; +18 mm Hg,
P
<0.01 in the elderly normotensive subjects; +19 mm Hg,
P
<0.001 in the hypertensive patients versus baseline). In the hypertensive subjects, the pressure increase persisted well into the recovery period. The pressure increase caused a significant increase in mean flow velocity in the middle cerebral arteries only in the elderly subjects. Cold pressor test increased blood pressure in all of the subjects during stimulation and the first 2 minutes of the recovery period (at whole-curve ANOVA: F=22.03,
P
<0.001 in the young participants; F=18.3,
P
<0.001 in the normotensive elderly; and F=13.04,
P
<0.001 in the hypertensive elderly). Mean flow velocity in the middle cerebral arteries significantly increased only in the hypertensive subjects. In the elderly hypertensive patients, the cerebrovascular reaction to adrenergic stimuli was more impaired than in the elderly normotensive subjects. This event can amplify the pressure insult on cerebral hemodynamics and increase the predisposition to cerebral damage, such as vascular cognitive impairment or stroke.
Influence of Salt Intake on Renin–Angiotensin and Natriuretic Peptide System Genes in Human Adipose Tissue
Authors: Engeli Stefan , Boschmann Michael , Frings Petra , Beck Luis , Janke Jürgen , Titze Jens , Luft Friedrich C. , Heer Martina , Jordan Jens
Published: October 2006

We tested the hypothesis that changes in sodium intake modulate adipose-tissue renin–angiotensin and natriuretic peptide system gene expression in humans. We studied 9 healthy young men in a metabolic ward at constant room temperature, humidity, and water, potassium, and calcium intake. Subjects were submitted to 4 different periods of sodium intake, and blood samples, microdialysis samples (interstitial fluid), and biopsies from subcutaneous abdominal adipose tissue were obtained at the end of the low-sodium period (0.7 mmol Na/kg per day) and at the end of the high-sodium period (7.7 mmol Na/kg per day). Urinary sodium excretion was 64±4 mmol per day with the low-sodium diet and 521±8 mmol per day with the high-sodium diet. Systemic and microdialysate sodium concentrations were similar with both interventions. With high-sodium intake, systemic renin activity and aldosterone levels were suppressed, angiotensin-converting enzyme activity did not change, and systemic levels of the atrial natriuretic peptide increased. High-sodium diet increased angiotensin-converting enzyme and atrial natriuretic peptide gene expression in adipose tissue. None of the other genes tested were influenced by changes in dietary sodium intake. Our findings suggest that the adipose-tissue renin–angiotensin system is not part of a feedback mechanism regulating sodium homeostasis and blood pressure. Systemic and adipose-tissue renin–angiotensin systems are regulated at least in part independently from each other. In contrast, systemic atrial natriuretic peptide and adipose-tissue atrial natriuretic peptide respond similarly to changes in sodium intake.
Serum Uric Acid Predicts Incident Hypertension in a Biethnic Cohort
Authors: Mellen Philip B. , Bleyer Anthony J. , Erlinger Thomas P. , Evans Gregory W. , Nieto F. Javier , Wagenknecht Lynne E. , Wofford Marion R. , Herrington David M.
Published: October 2006

Serum uric acid has been positively associated with incident hypertension, but previous studies have had limited ability to explore this relationship across sex and ethnic strata. We sought to evaluate this association in a biethnic cohort of middle-aged men and women. Participants in the Atherosclerosis Risk in Communities (ARIC) study who were free of hypertension at baseline (N=9104) were evaluated for hypertension at 3-year intervals over 4 examinations. Adjusted Cox proportional hazards models evaluated risk of incident hypertension or progression of blood category for each SD higher baseline serum uric acid. At baseline, the mean age was 53.3 years (range: 45 to 64 years), with a mean (SD) systolic blood pressure of 113.8 (12.2) mm Hg, mean diastolic blood pressure of 70.2 (8.6) mm Hg, and mean serum uric acid of 5.7 (1.4). Higher serum uric acid was associated with greater risk of hypertension in the overall cohort (hazard ratio for each SD of higher uric acid [95% CI]: 1.10 [1.04 to 1.15]) and in subgroup analyses (black men: 1.32 [1.14 to 1.54]; black women: 1.16 [1.03 to 1.31]; white men: 1.01 [0.94 to 1.09]; white women: 1.04 [0.96 to 1.11]), after adjustment for age, baseline blood pressure, body mass index, renal function, diabetes, and smoking. The pattern was similar when modeling blood pressure progression (overall: 1.10 [1.05 to 1.14]; black men: 1.26 [1.11 to 1.42]; black women: 1.18 [1.06 to 1.31]; white men: 1.05 [0.99 to 1.11]; white women: 1.05 [1.00 to 1.12]). In conclusion, serum uric acid was positively associated with incident hypertension over 9 years of follow-up, and this relationship was stronger in blacks than in whites. More research is warranted concerning the physiological and clinical consequences of hyperuricemia, especially in blacks.
Presence of a Ventricular Septal Defect and the Mustard Operation Are Risk Factors for Late Mortality After the Atrial Switch Operation
Authors: Lange Rüdiger , Hörer Jürgen , Kostolny Martin , Cleuziou Julie , Vogt Manfred , Busch Raymonde , Holper Klaus , Meisner Hans , Hess John , Schreiber Christian
Published: October 2006

Background—

Survival and functional status of patients with transposition of the great arteries treated by atrial switch are reported to be reasonably good within the first 15 postoperative years. However, in some patients, the function of the systemic right ventricle deteriorates, leading to significant morbidity or even to late mortality. This study seeks to identify risk factors for late death.

Methods and Results—

Records of 329 patients after the Senning operation and 88 after the Mustard operation at a single center were retrospectively reviewed for demographic, anatomic, and echocardiographic predictors and outcomes. Mean follow-up interval was 19.1±6.5 years and was 95% complete. Survival 25 years after the Mustard procedure was 75.9±4.8% and after the Senning procedure was 90.9±2.3% (
P
=0.002). Mustard patients died more often of arrhythmia than Senning patients (
P
<0.001) and needed more baffle-related reoperations (
P
<0.0001). Ventricular septal defect closure at the time of the atrial switch operation (hazard rate=2.3; 95% confidence interval, 1.1 to 4.7;
P
=0.025) and the Mustard operation (hazard rate=2.0; 95% confidence interval, 1.01 to 3.8;
P
=0.045) emerged as independent risk factors for late mortality in multivariate analysis. At follow-up, 85.8% of the patients led a normal life with full-time work, and 11.8% were able to do part-time work. Only 2.4% experienced noticeable limitation of activities.

Conclusions—

Our patient data reveal satisfactory results at long term in this historic collective. Patients who had undergone ventricular septal defect closure at the time of the atrial switch operation and those who had undergone a Mustard operation are at higher risk for late death. Close follow-up, especially of these subgroups, is warranted.
Mutant Caveolin-3 Induces Persistent Late Sodium Current and Is Associated With Long-QT Syndrome
Authors: Vatta Matteo , Ackerman Michael J. , Ye Bin , Makielski Jonathan C. , Ughanze Enoh E. , Taylor Erica W. , Tester David J. , Balijepalli Ravi C. , Foell Jason D. , Li Zhaohui , Kamp Timothy J. , Towbin Jeffrey A.
Published: October 2006

Background—

Congenital long-QT syndrome (LQTS) is a primary arrhythmogenic syndrome stemming from perturbed cardiac repolarization. LQTS, which affects ≈1 in 3000 persons, is 1 of the most common causes of autopsy-negative sudden death in the young. Since the sentinel discovery of cardiac channel gene mutations in LQTS in 1995, hundreds of mutations in 8 LQTS susceptibility genes have been identified. All 8 LQTS genotypes represent primary cardiac channel defects (ie, ion channelopathy) except LQT4, which is a functional channelopathy because of mutations in ankyrin-B. Approximately 25% of LQTS remains unexplained pathogenetically. We have pursued a “final common pathway” hypothesis to elicit novel LQTS-susceptibility genes. With the recent observation that the LQT3-associated,
SCN5A
-encoded cardiac sodium channel localizes in caveolae, which are known membrane microdomains whose major component in the striated muscle is caveolin-3, we hypothesized that mutations in caveolin-3 may represent a novel pathogenetic mechanism for LQTS.

Methods and Results—

Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, we performed open reading frame/splice site mutational analysis on
CAV3
in 905 unrelated patients referred for LQTS genetic testing.
CAV3
mutations were engineered by site-directed mutagenesis and the molecular phenotype determined by transient heterologous expression into cell lines that stably express the cardiac sodium channel hNa
v
1.5. We identified 4 novel mutations in
CAV3
-encoded caveolin-3 that were absent in >1000 control alleles. Electrophysiological analysis of sodium current in HEK293 cells stably expressing hNa
v
1.5 and transiently transfected with wild-type and mutant caveolin-3 demonstrated that mutant caveolin-3 results in a 2- to 3-fold increase in late sodium current compared with wild-type caveolin-3. Our observations are similar to the increased late sodium current associated with LQT3-associated
SCN5A
mutations.

Conclusions—

The present study reports the first
CAV3
mutations in subjects with LQTS, and we provide functional data demonstrating a gain-of-function increase in late sodium current.
Transthoracic Incremental Monophasic Versus Biphasic Defibrillation by Emergency Responders (TIMBER)
Authors: Kudenchuk Peter J. , Cobb Leonard A. , Copass Michael K. , Olsufka Michele , Maynard Charles , Nichol Graham
Published: October 2006

Background—

Although biphasic, as compared with monophasic, waveform defibrillation for cardiac arrest is increasing in use and popularity, whether it is truly a more lifesaving waveform is unproven.

Methods and Results—

Consecutive adults with nontraumatic out-of-hospital ventricular fibrillation cardiac arrest were randomly allocated to defibrillation according to the waveform from automated external defibrillators administered by prehospital medical providers. The primary event of interest was admission alive to the hospital. Secondary events included return of rhythm and circulation, survival, and neurological outcome. Providers were blinded to automated defibrillator waveform. Of 168 randomized patients, 80 (48%) and 68 (40%) consistently received only monophasic or biphasic waveform shocks, respectively, throughout resuscitation. The prevalence of ventricular fibrillation, asystole, or organized rhythms at 5, 10, or 20 seconds after each shock did not differ significantly between treatment groups. The proportion of patients admitted alive to the hospital was relatively high: 73% in monophasic and 76% in biphasic treatment groups (
P
=0.58). Several favorable trends were consistently associated with receipt of biphasic waveform shock, none of which reached statistical significance. Notably, 27 of 80 monophasic shock recipients (34%), compared with 28 of 68 biphasic shock recipients (41%), survived (
P
=0.35). Neurological outcome was similar in both treatment groups (
P
=0.4). Earlier administration of shock did not significantly alter the performance of one waveform relative to the other, nor did shock waveform predict any clinical outcome after multivariate adjustment.

Conclusions—

No statistically significant differences in outcome could be ascribed to use of one waveform over another when out-of-hospital ventricular fibrillation was treated.
Sirolimus-Eluting Stent Versus Paclitaxel-Eluting Stent for Patients With Long Coronary Artery Disease
Authors: Kim Young-Hak , Park Seong-Wook , Lee Seung-Whan , Park Duk-Woo , Yun Sung-Cheol , Lee Cheol Whan , Hong Myeong-Ki , Kim Hyun-Sook , Ko Jae-Ki , Park Jae-Hyeong , Lee Jae-Hwan , Choi Si Wan , Seong In-Whan , Cho Yoon Haeng , Lee Nae-Hee , Kim June Hong , Chun Kook-Jin , Park Seung-Jung
Published: October 2006

Background—

Outcomes remain relatively unfavorable for stent-based coronary intervention of lesions with long diseased segments. This study compared sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) for long coronary lesions.

Methods and Results—

The present randomized, multicenter, prospective study compared the use of long (≥32 mm) SES with PES in 500 patients with long (≥25 mm) native coronary lesions. The primary end point of the trial was the rate of binary in-segment restenosis according to follow-up angiography at 6 months. The SES and PES groups had similar baseline characteristics. Lesion length was 33.9±11.6 mm in the SES group and 34.5±12.6 mm in the PES group (
P
=0.527). The in-segment binary restenosis rate was significantly lower in the SES group than in the PES group (3.3% versus 14.6%; relative risk 0.23;
P
<0.001). In-stent late loss of lumen diameter was 0.09±0.37 mm in the SES group and 0.45±0.55 mm in the PES group (
P
<0.001). In patients with restenoses, a pattern of focal restenosis was more common in the SES group than in the PES group (100% versus 53.3%,
P
=0.031). Consequently, SES patients had a lower rate of target-lesion revascularization at 9 months (2.4% versus 7.2%,
P
=0.012). The incidence of death (0.8% in SES versus 0% in PES,
P
=0.499) or myocardial infarction (8.8% in SES versus 10.8% in PES,
P
=0.452) at 9 months of follow-up was not statistically different between the 2 groups.

Conclusions—

For patients with long native coronary artery disease, SES implantation was associated with a reduced incidence of angiographic restenosis and a reduced need for target-lesion revascularization compared with PES implantation.
Does Proportional Representation Foster Closer Congruence Between Citizens and Policy Makers?
Authors: Blais André , Bodet Marc André
Published: October 2006

This article assesses the claim that proportional representation (PR) fosters a closer correspondence between the views of citizens and the positions of the government. The study uses the Comparative Study of Electoral Systems data set and compares respondents’ self-placements on a Left-Right scale with placements of cabinet parties’ locations in 31 election studies. The authors argue that PR has two contradictory consequences. On one hand, PR leads to more parties and more choice for voters; but these parties are less centrist, and this increases the overall distance between voters and parties. On the other hand, PR increases the likelihood of coalition governments; this pulls the government toward the center of the policy spectrum and reduces the distance between the government and voters. These two contradictory effects of PR wash out, and the net overall impact of PR on congruence is nil. The data support the authors’ interpretation.
Noncoercive Mobilization in State-Controlled Elections
Authors: Guan Mei , Green Donald P.
Published: October 2006

China has gradually introduced a limited degree of democratization to its system of local governance, permitting self-nominated candidates for People’s Congress to campaign on their own behalf. Liberalization of elections has also meant that voters are less likely to be coerced into voting by their work groups. What are the likely consequences of liberalization for voter turnout rates in the future? The authors examine the effects of a noncoercive get-out-the-vote drive in one of the most highly liberalized electoral districts in China. A field experiment was conducted in a Peking University precinct during the 2003 election. Thousands of student voters were randomly assigned to control and treatment groups, the latter receiving encouragement to participate through door-to-door canvassing. These noncoercive mobilization efforts are found to be highly effective in raising voter turnout, suggesting that tactics used in open electoral systems may buoy voter turnout rates even as coercive mobilization tactics disappear.
The Impact of Economic Versus Institutional Factors in Elite Evaluations of Presidential Progress Toward Democracy in Latin America
Authors: Bishin Benjamin G. , Barr Robert R. , Lebo Matthew J.
Published: October 2006

Elites’ support for democracy and their satisfaction with political leadership are important factors in evaluating Latin American leaders’ progress toward consolidating their democracies. However, we know surprisingly little about how elites understand or define democracy and thereby evaluate leaders in terms of progress toward democracy. Much literature on opinions of elites focuses on their relative interest in democratic values and formal institutions. But is progress in these two areas really of utmost importance to elites? To better understand elite views of democracy, the authors use new survey data in which elites assess current politicians’ progress toward democracy. They find that the importance of perceived progress in democratic values—civil rights and civil liberties—and formal institutions is minor compared to the impact of perceptions of economic progress; elites’ evaluations of democratic progress depend primarily on their perceptions of economic success and only secondarily on perceptions of achievement of democratic values.
A systematic review of the relationship between socio-economic position and physical activity
Authors: Gidlow Christopher , Johnston Lynne Halley , Crone Diane , Ellis Naomi , James David
Published: October 2006

Objective The aim of the present review was to examine epidemiological evidence to determine if there is strong evidence of a positive gradient of increasing physical activity across the socio-economic strata, and how relationships are affected by socio-economic measurement.

Design Systematic review.

Method A search of major databases was conducted to identify published studies that reported physical activity in relation to socio-economic position (SEP) in adults.

Results Twenty-eight cross-sectional and five longitudinal studies met the inclusion criteria. Approximately half of these were American. Consequently education and income were most commonly used to represent SEP. The majority of studies were secondary analyses of existing health survey data, which could explain the generally large sample sizes and methodological weaknesses in physical activity and SEP measurement. There was consistent evidence of a higher prevalence or higher levels of leisure-time or moderate-vigorous intensity physical activity in those at the top of the socio-economic strata compared with those at the bottom. Evidence for positive gradients across the socio-economic strata was less consistent. Education produced the most stable relationships, less susceptible to confounding effects of ethnicity and the environment.

Conclusion Those at the top of the socio-economic scale appear to perform more leisure-time activity than those at the bottom. Diverse and often crude physical activity and socio-economic measurement made it difficult to distinguish between artefact and true effect in a relationship with so many potential confounding influences. Further studies using up-to-date methods of socio-economic and physical activity measurement are necessary to further explore this relationship and its confounders.
Three-dimensional Finite Element Frequency Domain Acoustic Analysis of Open Cell Plastics Foams
Authors: Tsay Huoy-Shyi
Published: October 2006

A numerical method using an impulsive excitation to excite and obtain the acoustic frequency response functions of isotropic open cell plastic foams is presented. The proposed three-dimensional finite element frequency domain acoustic analysis (3D FEFDAA) is first used to validate the acoustic properties of infinite planar and rigidly backed open cell plastic foam. Thereafter, the influences of fixed edge constraints and the width-to-thickness ratio on the acoustic properties of planar foam with finite width and length are examined. Furthermore, the use of 3D FEFDAA to predict the acoustic properties of the air layer and the pyramid foam is demonstrated. Without the use of the incident acoustic field that is required in the earlier studies, results predicted in the present study are shown to agree with the exact solutions.
Solid-state Processing of Polymer in the Presence of Supercritical Carbon Dioxide
Authors: Hu Xianbo , Lessery Alan J.
Published: October 2006

Open cell microporous bisphenol-A polycarbonate (PC) films are made by a novel, solvent-free processing: drawing PC in supercritical carbon dioxide (scCO2). The pore size is less than 1.0 m, and the porosity is in the range of 20-70% and is highly tunable. The porous film has mechanical properties nearly as high as the original film. The influence of temperature and pressure on drawability, porosity, and mechanical integrity are systematically studied.
Is Breast Milk Collected at Home Suitable for Raw Consumption by Neonates in Brazilian Public Neonatal Intensive Care Units?
Authors: de Almeida Castanho Rozolen Claudia Dardes , Goulart Ana Lucia , Kopelman Benjamin Israel
Published: October 2006

This study was designed to verify if breast milk collected at home is appropriate for raw consumption by neonates in a Brazilian public neonatal intensive care unit (NICU). From May 1998 to February 2000, microbiological characteristics of breast milk samples collected at home were analyzed. The milk samples were considered appropriate for raw consumption if mesophilic bacteria count was < 2500 CFU/mL and potential pathogens were not detected. Of 90 milk samples collected from 32 mothers of hospitalized neonates, 36 (40%) were rejected because of potentially pathogenic bacteria (72.2%), mesophilic bacteria count ≥ 2500 CFU/mL (13.9%), and both conditions (13.9%). The most frequent nonpathogenic and potentially pathogenic bacteria isolated were Staphylococcus coagulase negative and Klebsiella pneumoniae, respectively. Using univariate analysis, demographic, socioeconomic, educational, and house characteristics were not found to be associated with milk contamination. Breast milk collected at home may not be appropriate for raw consumption in Brazilian NICUs. Pasteurization could improve its microbiological quality. Further studies are needed.
Gabapentin and Breastfeeding: A Case Report
Authors: Kristensen Judith H. , Ilett Kenneth F. , Hackett L. Peter , Kohan Rolland
Published: October 2006

The aim of this study was to describe the milk-plasma ratio and relative infant dose of gabapentin in a breastfeeding mother and to determine the well-being of her exposed infant. The mother-infant pair was studied over a 24-hour dose interval at steady state. Gabapentin concentrations were quantified by high-performance liquid chromatography. Infant exposure was calculated as concentration in milk multiplied by an estimated milk production of 0.15 L/kg/d and normalized to the weight-adjusted maternal dose. The milk-plasma ratio was 0.86; the relative infant dose was 2.34%. The absolute infant dose was approximately 3% of the children’s dose for gabapentin, and the infant plasma level of 0.4 mg/L was approximately 6% of the maternal plasma drug concentration. No adverse effects attributable to gabapentin were noted in the infant. In combination with a previously published report, these limited data support the prescription of gabapentin to a breastfeeding mother after a careful individual risk-benefit analysis.
History, Physical and Laboratory Findings, and Clinical Outcomes of Lactating Women Treated With Antibiotics for Chronic Breast and/or Nipple Pain
Authors: Eglash Anne , Plane Mary Beth , Mundt Marlon
Published: October 2006

This chart review study describes the history, physical and laboratory findings, and clinical outcomes in patients who presented to a lactation specialist between 1997 and 2002 and were treated with antibiotics for their chronic breast and/or nipple pain. A total of 69 charts were reviewed. Five were excluded because of loss of follow-up. Eighty-two percent of patients described postpartum breast tenderness, 74% had nipple sores postpartum, and 79% were tender on physical examination. Nipple lesions were present among 73% of the women. Breast milk or nipple cultures were performed for 60 of 64 patients and were positive for pathogenic bacteria among 50% of the patients cultured. The average duration of antibiotic treatment was 5.7 weeks, and 94% of the women had pain resolution. Symptoms of deep breast aching, breast tenderness on palpation, and nipple lesions may be suggestive of a bacterial lactiferous duct infection. Treatment with antibiotics for 4 to 6 weeks may be appropriate.
The Impact of a New Universal Postpartum Program on Breastfeeding Outcomes
Authors: Sheehan Debbie , Watt Susan , Krueger Paul , Sword Wendy
Published: October 2006

The Ontario Mother and Infant Study II examined changes in postpartum health outcomes, including breastfeeding initiation and discontinuation, for mothers and their infants and compared these results to data collected prior to the initiation of the Universal Hospital Stay and Postpartum Home Visiting Program policy change in 1998. Data were collected using cross-sectional surveys before discharge and at 4 weeks postdischarge. Ninety percent of the women surveyed at 4 weeks postpartum initiated breastfeeding. Of these, 84% were still breastfeeding at 4 weeks postpartum. None of the 3 major program components—extended length of stay, a postpartum phone call from a public health worker, or a postpartum in-home visit—were associated with breastfeeding continuation to 4 weeks. Discontinuation before 4 weeks postdischarge was associated with maternal attitudes toward breastfeeding, formula feeding or supplementation in hospital, infant readmission, and use of walk-in clinics for infant care.
Staffing for Hospital Lactation Programs: Recommendations From a Tertiary Care Teaching Hospital
Authors: Mannel Rebecca , Mannel Robert S.
Published: October 2006

A retrospective review of data from a lactation program’s productivity reports at a large tertiary care teaching hospital (4200 births per year) measured actual hours worked by international board certified lactation consultants (IBCLCs) over a 2-year period, allocated the hours to their respective activities, and developed ratios for optimal IBCLC staffing for each component of service delivered. Optimal IBCLC staffing was calculated as follows: mother/baby inpatient requires 1 full-time equivalent (FTE) per 783 breastfeeding couplets; neonatal intensive care unit (NICU) inpatient requires 1 FTE per 235 infant admits; mother/baby outpatient requires 1 FTE per 1292 breastfeeding couplets discharged; NICU outpatient requires 1 FTE per 818 breastfeeding infants discharged; telephone follow-up requires 1 FTE per 3915 breastfeeding couplets or infants discharged; education requires 0.1 FTE per 1000 deliveries; program development/administration requires 0.1 FTE per 1000 deliveries; and research requires 0.1 to 0.2 FTE total. Using the formulas provided, IBCLC staffing can be calculated for desired services based on patient numbers.
Studies on the Synthesis and Characterization of Diglycidylether-terminated Polydimethyl Siloxane-modified Epoxy-Bismaleimide Matrices
Authors: Kumar Ramasamy Suresh , Alagar Muthukaruppan
Published: October 2006

Diglycidylether-terminated polydimethylsiloxane (DGETPDMS) toughened epoxy matrix systems were developed and further modified with bismaleimide (BMI), namely N, N‘-bismaleimido-4,4‘-diphenylsulfone. The matrix systems were cured using 4,4‘-diaminodiphenylmethane (DDM) as curing agent. The mechanical, thermal, and electrical properties were studied by standard test methods. The introduction of DGETPDMS into epoxy resin improved the impact strength with reduction of tensile strength, flexural strength and glass transition temperature in comparison with the unmodified epoxy, whereas the incorporation of BMI into epoxy resin improved tensile strength, flexural strength, glass transition temperature and heat distortion temperature in comparison with the unmodified epoxy resin. The incorporation of BMI into DGETPDMS-modified epoxy resin improved thermal stability, dielectric strength, surface resistivity, and arc resistance with increasing loading level. SEM micrographs of both BMI-modified epoxy and BMI-modified DGETPDMS-epoxy systems exhibited homogeneous morphology.