bluuebunny/crossref_metadata_2025 huggingface dataset:
Stability and Bifurcation Analysis in a Class of Two‐Neuron Networks with Resonant Bilinear Terms
Authors: Xu Changjin , He Xiaofei
Published: June 2011

A class of two‐neuron networks with resonant bilinear terms is considered. The
stability of the zero equilibrium and existence of Hopf bifurcation is studied. It is shown that the zero
equilibrium is locally asymptotically stable when the time delay is small enough, while change of stability
of the zero equilibrium will cause a bifurcating periodic solution as the time delay passes through a
sequence of critical values. Some explicit formulae for determining the stability and the direction of the
Hopf bifurcation periodic solutions bifurcating from Hopf bifurcations are obtained by using the normal
form theory and center manifold theory. Finally, numerical simulations supporting the theoretical analysis
are carried out.
Effect of Preoperative N-Acetylcysteine on Postoperative Blood Loss Parameters in Cardiac Surgery Patients
Authors: Wesner Amber R. , Brackbill Marcia L. , Sytsma Christine S.
Published: June 2011

Purpose. To determine if recent preoperative exposure to n-acetylcysteine (NAC), Mucomyst, increases postoperative blood loss in cardiac surgery patients.Methods. Retrospective review of cardiac surgery patients who underwent a cardiac catheterization within four days of surgery and whose serum creatinine was ≥1.0 mg/dL. The study groups were those who received NAC in the pericatheterization period versus those who did not. The primary endpoint was postoperative chest tube output at 24, 48, and 72 hours. Secondary endpoints included number of transfusions and other bleeding parameters.Results. Mean blood loss in the first 24 hours was 962 ± 595 mL in the treatment group (n=79) and 1,178 ± 788 mL in the control group (n=106),P=.040. Blood loss between groups at 48 (366 ± 318 mL versus 412 ± 363 mL,P=.382) and 72 (194 ± 300 mL versus 176 ± 224 mL,P=.643) hours was not significantly different. There were no significant differences in postoperative transfusions or other bleeding parameters.Conclusions. Preoperative exposure to NAC did not increase postoperative blood loss or negatively affect other bleeding parameters.
Suppressors of Cytokine Signaling 3 Expression in Eosinophils: Regulation by PGE2and Th2 Cytokines
Authors: López Esther , Zafra María Paz , Sastre Beatriz , Gámez Cristina , Fernández-Nieto Mar , Sastre Joaquín , Lahoz Carlos , Quirce Santiago , Del Pozo Victoria
Published: June 2011

Asthma and nonasthmatic eosinophilic bronchitis (NAEB) are respiratory disorders characterized by a predominance of Th2 cells and eosinophilic inflammation. Suppressors of cytokine signaling (SOCS) proteins play an important role in Th2-mediated allergic responses through control of the balance between Th1 and Th2 cells, particularly, SOCS3 and SOCS5. The aim of this study was to analyze SOCS expression in human peripheral blood eosinophils from patients with asthma, NAEB and healthy controls. SOCS expression in eosinophils from subjects was demonstrated by different techniques. Results showed that expression of SOCS3 in eosinophils and CD4 T cells from patients was higher than in healthy subjects. In addition, we demonstrated that prostaglandin E2(PGE2) and Th2 cytokines are able to upregulate SOCS3 production in eosinophils and attenuate its degranulation. In conclusion, eosinophils are able to transcribe and translate SOCS3 protein and can contribute to the regulation of the Th1/Th2 balance through SOCS3 production.
An Extract ofGlycyrrhiza glabra(GutGard) Alleviates Symptoms of Functional Dyspepsia: A Randomized, Double-Blind, Placebo-Controlled Study
Authors: Raveendra Kadur Ramamurthy , Jayachandra  , Srinivasa Venkatappa , Sushma Kadur Raveendra , Allan Joseph Joshua , Goudar Krishnagouda Shankargouda , Shivaprasad Hebbani Nagarajappa , Venkateshwarlu Kudiganti , Geetharani Periasamy , Sushma Gopalakrishna , Agarwal Amit
Published: June 2011

A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of GutGard, an extract ofGlycyrrhiza glabra, in patients with functional dyspepsia. The primary outcome variables of the study were the change in the severity symptoms and the global assessment of efficacy. The quality of life was evaluated as a secondary outcome measure. The patients received either placebo or GutGard (75 mg twice daily) for 30 days. Efficacy was evaluated in terms of change in the severity of symptoms (as measured by 7-point Likert scale), the global assessment of efficacy, and the assessment of quality of life using the short-form Nepean Dyspepsia Index. In comparison with placebo, GutGard showed a significant decrease (P≤.05) in total symptom scores on day 15 and day 30, respectively. Similarly, GutGard showed marked improvement in the global assessment of efficacy in comparison to the placebo. The GutGard group also showed a significant decrease (P≤.05) in the Nepean dyspepsia index on day 15 and 30, respectively, when compared to placebo. GutGard was generally found to be safe and well-tolerated by all patients. GutGard has shown significant efficacy in the management of functional dyspepsia.
Adoptive Transfer of Tumor Reactive B Cells Confers Host T-Cell Immunity and Tumor Regression
Authors: Li Qiao , Lao Xiangming , Pan Qin , Ning Ning , Yet Ji , Xu Yingxin , Li Shengping , Chang Alfred E.
Published: June 2011

Purpose: We investigated the antitumor reactivity of adoptively transferred effector B cells and the mechanisms by which they may mediate tumor regression in a spontaneous metastases model.

Experimental Design: 4T1 breast cancer cells were inoculated into the flanks of syngeneic Balb/C mice to prime draining lymph nodes. Tumor-draining lymph nodes (TDLN) were harvested and B cells activated ex vivo with lipopolysaccharide and anti-CD40 monoclonal antibody. These activated B cells were adoptively transferred into mice inoculated with 4T1 tumor in the mammary fat pad. The induction of host T-cell immunity was evaluated.

Results: Activated 4T1 TDLN B cells secreted immunoglobulin G (IgG) in response to tumor cells which was immunologically specific. These activated B cells were capable of mediating specific lysis of tumor cells in vitro. Transfer of these activated B cells alone mediated the inhibition of spontaneous metastases to the lung. Examination of the host revealed that the transfer of these B cells resulted in the induction of tumor-specific T-cell immunity as measured by cytotoxicity and cytokine (IFNγ and granulocyte-macrophage colony-stimulating factor) production. The combined transfer of activated T and B cells from TDLN resulted in tumor regression, which was greater than either cell population alone, with host B cells capable of producing IgG that mediated lysis of tumor in the presence of complement.

Conclusions: We have found that appropriately primed B cells can mediate tumor regression by itself and confers host T-cell antitumor immunity. Furthermore, effector B cells can serve as a useful adjunct in adoptive T-cell therapy. Clin Cancer Res; 17(15); 4987–95. ©2011 AACR.
Enhancement of 5-Fluorouracil-induced In Vitro and In Vivo Radiosensitization with MEK Inhibition
Authors: Urick Mary Ellen , Chung Eun Joo , Shield William P. , Gerber Naamit , White Ayla , Sowers Anastasia , Thetford Angela , Camphausen Kevin , Mitchell James , Citrin Deborah E.
Published: June 2011

Purpose: Gastrointestinal cancers frequently exhibit mutational activation of the Ras/MAPK pathway, which is implicated in resistance to ionizing radiation (IR) and chemotherapy. Concurrent radiotherapy and 5-fluorouracil (5-FU) based chemotherapy is commonly used for treatment of gastrointestinal malignancies. We previously reported radiosensitization with selumetinib, an inhibitor of MEK1/2. The purpose of the current study was to evaluate if selumetinib could enhance radiosensitivity induced by 5-FU.

Experimental Design: Clonogenic survival assays were carried out with the HT29 (colorectal), HCT116 (colorectal), and MiaPaca-2 (pancreatic) cell lines using pre-IR treatment with selumetinib, 5-FU and 5-FU+selumetinib. Cell proliferation was determined using a tetrazolium conversion assay. Mitotic catastrophe and DNA repair were analyzed using immunocytochemistry. Flow cytometry was used to analyze cell cycle and apoptosis. Growth delay was used to determine effects of 5-FU+selumetinib on in vivo tumor radiosensitivity.

Results: Pre-IR treatment with 5-FU+selumetinib significantly decreased clonogenic survival compared with either agent alone. Dose modifying factors at a surviving fraction of 0.1 for 5-FU+selumetinib was 1.78, 1.52, and 1.3 for HT29, HCT116, and MiaPaca-2, respectively. Cell proliferation was decreased by treatment with selumetinib+5-FU as compared with single agent treatment regardless of treatment sequencing. Enhancement of 5-FU cytotoxicity and 5-FU mediated radiosensitization with selumetinib treatment was accompanied by an increase in mitotic catastrophe and apoptosis, and reductions in Stat3 phosphorylation and survivin expression. In vivo, an additive growth delay was observed with 5-FU+selumetinib+3Gy versus 5-FU+3Gy and selumetinib alone.

Conclusion: These data suggest that selumetinib can be used with 5-FU to augment radiation response. Clin Cancer Res; 17(15); 5038–47. ©2011 AACR.
p53 Expression in Node-Positive Breast Cancer Patients: Results from the Cancer and Leukemia Group B 9344 Trial (159905)
Authors: Lara Jonathan F. , Thor Ann D. , Dressler Lynn G. , Broadwater Gloria , Bleiweiss Ira J. , Edgerton Susan , Cowan David , Goldstein Lori J. , Martino Silvana , Ingle James N. , Henderson I. Craig , Norton Larry , Winer Eric P. , Hudis Clifford A. , Ellis Matthew J. , Berry Donald A. , Hayes Daniel F. ,   for the Cancer and Leukemia Group B
Published: June 2011

Purpose: p53 as a prognostic and predictive factor in early-stage breast cancer has had mixed results. We studied p53 protein expression, by immunohistochemistry, in a randomized clinical trial of stage II patients treated with adjuvant doxorubicin and cyclophosphamide with or without paclitaxel [Cancer and Leukemia Group B (CALGB) 9344, INT0148].

Patients and Methods: Epithelial p53 expression was evaluated using two immunohistochemical antibodies (DO7 and 1801) in formalin-fixed, paraffin-embedded tissue from patients with node-positive breast cancer who were randomized to four cycles of cyclophosphamide and one of three doses of doxorubicin (60, 75, or 90 mg/m2; AC) and to receive four subsequent cycles of paclitaxel (T) or not. Prognostic and predictive value of p53 protein expression was assessed, independent of treatment assignment, for escalating doses of doxorubicin or addition of T with endpoints of relapse-free (RFS) and overall survival (OS).

Results: Of 3,121 patients, 1,887 patient specimens treated on C9344 were obtained, passed quality control, and evaluated for p53 expression. Expression was 23% and 27% for mAbs 1801 and D07, respectively, with 92% concordance. In univariate analysis, p53 positivity was associated with worse OS with either antibody, but only p53 staining with monoclonal antibody 1801 had significantly worse RFS. In multivariate analysis, p53 was not predictive of RFS or OS from either doxorubicin dose escalation or addition of paclitaxel regardless of the antibody.

Conclusion: Nuclear staining of p53 by immunohistochemistry is associated with worse prognosis in node-positive patients treated with adjuvant doxorubicin-based chemotherapy but is not a useful predictor of benefit from doxorubicin dose escalation or the addition of paclitaxel. Clin Cancer Res; 17(15); 5170–8. ©2011 AACR.
Class III β-Tubulin in Advanced NSCLC of Adenocarcinoma Subtype Predicts Superior Outcome in a Randomized Trial
Authors: Vilmar Adam Christian , Santoni-Rugiu Eric , Sørensen Jens Benn
Published: June 2011

Purpose: Platinum-based doublets are the cornerstone of treatment in advanced non–small-cell lung cancer (NSCLC) and often include vinorelbine or taxanes. A predictive biomarker is greatly needed to select chemotherapy-sensitive patients for these microtubule-interfering agents. Class III β-tubulin (TUBB3) has been shown of value in NSCLC, but evidence is not uniform. Accordingly, we explored the predictive role of TUBB3 in advanced NSCLC.

Experimental Design: Four hundred forty-three patients with advanced NSCLC were enrolled in a phase III trial and randomized to vinorelbine- or paclitaxel-containing chemotherapy. Immunohistochemical evaluation of TUBB3 status was mainly done on bioptic material and correlated to response rates, progression-free survival (PFS), overall survival (OS), quality of life (QOL), and toxicity.

Results: Two hundred sixty-one (58.9%) patients had representative tissue samples for TUBB3 evaluation. Patients with TUBB3-negative adenocarcinomas had a significantly prolonged PFS and OS when compared with the opposite subgroup (7.87 vs. 6.83 months, P = 0.035 and 14.17 vs. 11.17 months, P = 0.018, respectively). Multivariate analyses revealed an HR of 1.55 (95% CI, 1.04–2.31, P = 0.032) for TUBB3-positive adenocarcinoma patients. TUBB3-negative adenocarcinoma patients showed a mean QOL decline of −18.25 points (95% CI, −4.28 to −32.22, P = 0.013) as compared with −3.86 (95% CI, −7.0 to 15.52, P = 0.5).

Conclusion: TUBB3 was of predictive value in adenocarcinoma patients in the largest, randomized advanced NSCLC population published to date. It may be clinically useful in conjunction with other biomarkers, but QOL information should be recorded during validation, as prophylactic intervention may be needed in specific subgroups at risk of toxicity. Clin Cancer Res; 17(15); 5205–14. ©2011 AACR.
Clinical, Pharmacodynamic, and Pharmacokinetic Evaluation of BNC105P: A Phase I Trial of a Novel Vascular Disrupting Agent and Inhibitor of Cancer Cell Proliferation
Authors: Rischin Danny , Bibby David C. , Chong Geoff , Kremmidiotis Gabriel , Leske Annabell F. , Matthews Clayton A. , Wong Shirley S. , Rosen Mark A. , Desai Jayesh
Published: June 2011

Purpose: To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects.

Experimental Design: BNC105P was administered as a 10-minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker.

Results: Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1–18.9 mg/m2). The recommended dose level was 16 mg/m2 and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects.

Conclusions: BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m2 and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced. Clin Cancer Res; 17(15); 5152–60. ©2011 AACR.
Use of Emergency Medical Service Transport Among Patients With ST-Segment–Elevation Myocardial Infarction
Authors: Mathews Robin , Peterson Eric D. , Li Shuang , Roe Matthew T. , Glickman Seth W. , Wiviott Stephen D. , Saucedo Jorge F. , Antman Elliott M. , Jacobs Alice K. , Wang Tracy Y.
Published: June 2011

Background—

Activation of emergency medical services (EMS) is critical for the early triage and treatment of patients experiencing ST-segment–elevation myocardial infarction, yet data regarding EMS use and its association with subsequent clinical care are limited.

Methods and Results—

We performed an observational analysis of 37 634 ST-segment–elevation myocardial infarction patients treated at 372 US hospitals participating in the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines between January 2007 and September 2009, and examined independent patient factors associated with EMS transportation versus patient self-transportation. We found that EMS transport was used in only 60% of ST-segment–elevation myocardial infarction patients. Older patients, those living farther from the hospital, and those with hemodynamic compromise were more likely to use EMS transport. In contrast, race, income, and education level did not appear to be associated with the mode of transport. Compared with self-transported patients, EMS-transported patients had significantly shorter delays in both symptom-onset-to-arrival time (median, 89 versus 120 minutes;
P
<0.0001) and door-to-reperfusion time (median door-to-balloon time, 63 versus 76 minutes;
P
<0.0001; median door-to-needle time, 23 versus 29 minutes;
P
<0.0001).

Conclusions—

Emergency medical services transportation to the hospital is underused among contemporary ST-segment–elevation myocardial infarction patients. Nevertheless, use of EMS transportation is associated with substantial reductions in ischemic time and treatment delays. Community education efforts are needed to improve the use of emergency transport as part of system-wide strategies to improve ST-segment–elevation myocardial infarction reperfusion care.
Secondary Prevention and Mortality in Peripheral Artery Disease
Authors: Pande Reena L. , Perlstein Todd S. , Beckman Joshua A. , Creager Mark A.
Published: June 2011

Background—

Whether individuals with peripheral artery disease (PAD) identified by screening ankle-brachial index benefit from preventive therapies to reduce cardiovascular risk is unknown. We aimed to determine the number of US adults with PAD who are not receiving preventive therapies and whether treatment is associated with reduced mortality in PAD subjects without known cardiovascular disease.

Methods and Results—

We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 with mortality follow-up through December 31, 2006. We defined PAD as an ankle-brachial index ≤0.90. Of 7458 eligible participants ≥40 years, weighted PAD prevalence was 5.9±0.3% (mean±SE), corresponding to ≈7.1 million US adults with PAD. Statin use was reported in only 30.5±2.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in 24.9±1.9%, and aspirin use in 35.8±2.9%, corresponding to 5.0 million adults with PAD not taking statins, 5.4 million not taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 4.5 million not receiving aspirin. After adjustment for age, sex, and race/ethnicity, PAD was associated with all-cause mortality (hazard ratio, 2.4; 95% confidence interval, 1.9 to 2.9;
P
<0.0001). Even after exclusion of individuals with known cardiovascular disease, subjects with PAD had higher mortality rates (16.1±2.1%) than subjects without PAD or cardiovascular disease (4.1±0.3%), with an adjusted hazard ratio of 1.9 (95% confidence interval, 1.3 to 2.8;
P
=0.001). Among PAD subjects without cardiovascular disease, use of multiple preventive therapies was associated with 65% lower all-cause mortality (hazard ratio, 0.35; 95% confidence interval, 0.20 to 0.86;
P
=0.02).

Conclusions—

Millions of US adults with PAD are not receiving secondary prevention therapies. Treatment with multiple therapies is associated with reduced all-cause mortality.
Peroxisome Proliferator–Activated Receptor-γ Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells
Authors: Tobiasova Zuzana , Zhang Lufeng , Yi Tai , Qin Linfeng , Manes Thomas D. , Kulkarni Sanjay , Lorber Marc I. , Rodriguez Frederick C. , Choi Je-Min , Tellides George , Pober Jordan S. , Kawikova Ivana , Bothwell Alfred L.M.
Published: June 2011

Background—

Ligands activating the transcription factor peroxisome proliferator–activated receptor-γ (PPARγ) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPARγ agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPARγ in human transplantation are unknown.

Methods and Results—

We tested the effects of PPARγ agonists on human vascular graft rejection using a model in which human artery is interposed into the abdominal aorta of immunodeficient mice, followed by adoptive transfer of allogeneic (to the artery donor) human peripheral blood mononuclear cells. Interferon-γ–dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPARγ agonists 15-deoxy-prostaglandin-J
2
, ciglitazone, and pioglitazone reduced intimal expansion, intimal infiltration of CD45RO
+
memory T cells, and plasma levels of inflammatory cytokines. The PPARγ antagonist GW9662 reversed the protective effects of PPARγ agonists, confirming the involvement of PPARγ-mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPARγ effects.

Conclusion—

Our results suggest that PPARγ agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection.
Increased Risk for Heart Valve Disease Associated With Antiphospholipid Antibodies in Patients With Systemic Lupus Erythematosus
Authors: Zuily S. , Regnault V. , Selton-Suty C. , Eschwège V. , Bruntz J.-F. , Bode-Dotto E. , De Maistre E. , Dotto P. , Perret-Guillaume C. , Lecompte T. , Wahl D.
Published: June 2011

Background—

Heart valve disease (HVD) is frequent in patients with systemic lupus erythematosus (SLE), and the role of antiphospholipid antibodies (aPL) is controversial. Thus, our objective was to estimate the risk of HVD, including Libman-Sacks endocarditis, associated with aPL in patients with SLE.

Methods and Results—

Studies were selected if they investigated the association between aPL and HVD in SLE patients and if aPL-negative patients were included for comparison. Data sources were MEDLINE, Embase, Cochrane Library, hand search, contact with investigators, and reference lists of studies, without language restrictions. Data on study and patient characteristics, risk estimates, and study quality were independently extracted by 2 investigators. Pooled effect estimates were obtained by using the DerSimonian-Laird method. Of 234 identified abstracts, 23 primary studies (15 cross-sectional, 7 cohort, 1 case-control) met inclusion criteria, including 1656 SLE patients and 508 cases of HVD. Compared with SLE patients without aPL (n=988), the overall pooled odds ratios for HVD and Libman-Sacks endocarditis in aPL-positive patients (n=668) were 3.13 (95% confidence interval, 2.31 to 4.24) and 3.51 (95% confidence interval, 1.93 to 6.38), respectively. The risk of HVD depending on aPL subtypes was the highest for lupus anticoagulant at 5.88 (95% confidence interval, 2.92 to 11.84) and IgG anticardiolipin antibodies at 5.63 (95% confidence interval, 3.53 to 8.97).

Conclusions—

Overall, the presence of aPL in SLE patients is significantly associated with an increased risk for HVD including Libman-Sacks endocarditis. The risk conferred by IgG anticardiolipin antibodies is as strong as by lupus anticoagulant. Systematic echocardiographic examinations in SLE patients with aPL should be performed.
Impact of Leptin-Mediated Sympatho-Activation on Cardiovascular Function in Obese Mice
Authors: Belin de Chantemèle Eric J. , Mintz James D. , Rainey William E. , Stepp David W.
Published: June 2011

Although the anorexic effects of leptin are lost in obesity, leptin-mediated sympatho-activation is preserved. The cardiovascular consequences of leptin-mediated sympatho-activation in obesity are poorly understood. We tested the hypothesis that 32 weeks of high-fat diet (HFD) induces metabolic leptin resistance but preserves leptin-mediated sympatho-activation of the cardiovascular system. HFD in mice significantly increased body weight and plasma leptin concentrations but significantly reduced the anorexic effects of leptin. HFD increased heart rate, stroke volume, cardiac output, and plasma aldosterone levels but not blood pressure. As reflected by the contractile response to phenylephrine measured both in vivo and ex vivo, vascular adrenergic reactivity was reduced by HFD, suggesting that reductions in sympathetic tone to the periphery vasculature may mitigate sympatho-activation of the heart and the renin-angiotensin-aldosterone system. Tachyphylaxis was partially restored by symptho-inhibition and not present in ob/ob and db/db mice, despite obesity, arguing for a sympatho-mediated and leptin-specific mechanism. Although infusion of leptin in HFD mice had no effect on heart rate or blood pressure, it further increased aldosterone levels and further reduced vascular adrenergic tone in the absence of weight loss, indicating persistent leptin-mediated stimulation of the cardiovascular system in obesity. In conclusion, these data indicate that, despite metabolic leptin resistance, leptin-mediated stimulation of the heart, the vasculature, and aldosterone production persists in obesity. Blood pressure effects in response to leptin may be limited by a tachyphylactic response in the circulation, suggesting that failure of adrenergic desensitization may be a requisite step for hypertension in the context of obesity.
Exercise Training Versus Propranolol in the Treatment of the Postural Orthostatic Tachycardia Syndrome
Authors: Fu Qi , VanGundy Tiffany B. , Shibata Shigeki , Auchus Richard J. , Williams Gordon H. , Levine Benjamin D.
Published: June 2011

We have found recently that exercise training is effective in the treatment of the postural orthostatic tachycardia syndrome (POTS). Whether this nondrug treatment is superior to “standard” drug therapies, such as β-blockade, is unknown. We tested the hypothesis that exercise training but not β-blockade treatment improves symptoms, hemodynamics, and renal-adrenal responses in POTS patients. Nineteen patients (18 women and 1 man) completed a double-blind drug trial (propranolol or placebo) for 4 weeks, followed by 3 months of exercise training. Fifteen age-matched healthy individuals (14 women and 1 man) served as controls. A 2-hour standing test was performed before and after drug treatment and training. Hemodynamics, catecholamines, plasma renin activity, and aldosterone were measured supine and during 2-hour standing. We found that both propranolol and training significantly lowered standing heart rate. Standing cardiac output was lowered after propranolol treatment (
P
=0.01) but was minimally changed after training. The aldosterone:renin ratio during 2-hour standing remained unchanged after propranolol treatment (4.1±1.7 [SD] before versus 3.9±2.0 after;
P
=0.46) but modestly increased after training (5.2±2.9 versus 6.5±3.0;
P
=0.05). Plasma catecholamines were not affected by propranolol or training. Patient quality of life, assessed using the 36-item Short-Form Health Survey, was improved after training (physical functioning score 33±10 before versus 50±9 after; social functioning score 37±9 versus 48±6; both
P
<0.01) but not after propranolol treatment (34±10 versus 36±11,
P
=0.63; 39±7 versus 39±5,
P
=0.73). These results suggest that, for patients with POTS, exercise training is superior to propranolol at restoring upright hemodynamics, normalizing renal-adrenal responsiveness, and improving quality of life.
Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia
Authors: McCarthy Fergus P. , Drewlo Sascha , Kingdom John , Johns Edward J. , Walsh Sarah K. , Kenny Louise C.
Published: June 2011

Preeclampsia is a multisystemic disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. It is a major cause of maternal and perinatal morbidity and mortality and is thought to be attributable, in part, to inadequate trophoblast invasion. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-activated transcription factor expressed in trophoblasts, and the vasculature of which activation has been shown to improve endothelium-dependent vasodilatation in hypertensive conditions. We investigated the effects of the administration of a PPAR-γ agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-γ agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-γ activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tin-protoporphyrin IX. RUPP rats were characterized by hypertension, endothelial dysfunction, and elevated microalbumin:creatinine ratios. Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin:creatinine ratio in RUPP rats. With the exception of microalbumin:creatinine ratio, these beneficial effects were abrogated in the presence of the heme oxygenase 1 inhibitor. Administration of a PPAR-γ agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of preeclampsia, via a heme oxygenase 1–dependent pathway. The findings from this study provide further insight into the underlying etiology of preeclampsia and a potential therapeutic target for the treatment of preeclampsia.
Erythropoietin Increases Expression and Function of Transient Receptor Potential Canonical 5 Channels
Authors: Liu Ying , Xu Yunfei , Thilo Florian , Friis Ulla G. , Jensen Boye L. , Scholze Alexandra , Zheng Junhua , Tepel Martin
Published: June 2011

Hypertension is a common complication in hemodialysis patients during erythropoietin (EPO) treatment. The underlying mechanisms of EPO-induced hypertension still remain to be determined. Increased transient receptor potential canonical (TRPC) channels have been associated with hypertension. Now, TRPC gene expression was investigated using quantitative real-time RT-PCR and immunoblotting in cultured human endothelial cells and in monocytes from hemodialysis patients. EPO dose-dependently increased TRPC5 mRNA in endothelial cells. EPO increased TRPC5 mRNA stability, that is, EPO prolonged the half-life period for TRPC5 mRNA from 16 hours (control) to 24 hours (
P
<0.05). The poly(A) tail length was measured by rapid amplification of cDNA ends-poly(A) test. Increased TRPC5 mRNA stability was attributed to longer 3′ poly(A) tail lengths after EPO administration. EPO also significantly increased TRPC5 channel protein abundance by 70% (
P
<0.05). Whole-cell patch clamp showed that angiotensin II–induced, TRPC5-mediated currents were dramatically increased in endothelial cells treated with EPO. Fluorescent dye techniques confirmed that increased calcium influx after EPO treatment was abolished after TRPC5 knockdown (
P
<0.05). EPO also significantly increased intracellular reactive oxygen species production. Knockdown of TRPC5 alleviated EPO-induced reactive oxygen species generation in endothelial cells (
P
<0.05). In vivo, EPO-treated hemodialysis patients showed significantly increased amounts of TRPC5 mRNA in monocytes compared with EPO-free hemodialysis patients (6.0±2.4 [n=12] versus 1.0±0.5 [n=9];
P
<0.01). Patients undergoing EPO treatment also showed significantly elevated systolic blood pressure (160±7 versus 139±6 mm Hg;
P
<0.05). Our findings suggest that upregulated functional TRPC5 gene may be one cause of EPO-induced hypertension in patients with chronic kidney disease.
Health literacy screening of geriatric monolingual Spanish-speaking patients using single-item literacy screening questions and education
Authors: Cordasco Kristina M , Homeier Diana C , Franco Idalid , Wang Pin-Chieh , Sarkisian Catherine A
Published: June 2011

Objective:

We describe the performance of Single Item Literacy Screener (SILS) questions, and educational attainment, as screening for inadequate health literacy (IHL) in older monolingual Spanish speakers.

Design:

We used a cross-sectional design, interviewing participants once at the time of their arrival for a clinic appointment.

Setting:

We conducted this study in primary care and geriatrics clinics in an urban US safety-net hospital.

Method:

We conducted in-person interviews with older monolingual Spanish-speaking diabetes patients, comparing responses to three SILS questions, and education, to shortened Test of Functional Health Literacy in Adults (sTOFHLA) scores. We calculated sensitivities, specificities and areas under the receiving–operator characteristic (AUROC) curve.

Results:

We interviewed 160 patients – 134 (84%) had IHL by sTOFHLA scores. The best performing SILS question, ‘How confident are you filling out medical forms by yourself?’ had an AUROC curve of 0.82 (95% CI 0.75–0.89). Using this question’s most stringent cut-off, sensitivity was 0.93 (95% CI 0.89–0.97); specificity was 0.27 (95% CI 0.20–0.34). The other two SILS questions had AUROC curves less than 0.50. The educational achievement AUROC curve was 0.88 (95% CI 0.78–0.97); using an education cut-off of six years or less had a specificity to 0.81 (95% CI 0.75–0.87) and sensitivity of 0.83 (95% CI 0.77–0.89).

Conclusion:

Clinicians and investigators considering using single items as screeners for IHL in older US monolingual Spanish speakers should either use the ‘confidence with forms’ SILS, being aware of its specificity limitations, or a single question assessing educational achievement.
Learning through conversation: Exploring and extending teacher and children’s involvement in classroom talk
Authors: Brown Kirsty , Kennedy Hilary
Published: June 2011

This article details a professional development process with a group of teachers and educational psychologists in the UK, at a school for children identified as having social, emotional, and behavioural difficulties. The project focused on how teachers use conversation to include children within dialogue and incorporate children’s ideas within the learning process. Through reflective and exploratory discussion, enhanced by videos of interactive sequences within classes, teachers explored and developed aspects of their interactional styles. Videos were compared from the beginning and end of the project showing considerable changes in how teachers and children participated in classroom conversations. Changes included the teachers using conversation to build more on children’s ideas and actively support the cooperation between children. Changes in the nature of talk amongst children showed evidence of building more on ideas within conversations and making less new initiatives. The changes in conversations are considered with reference to children’s participation and learning. Educational psychologists working alongside teachers in this way allowed assessment and intervention to occur at whole class and school level. The process of collaboration with teachers is considered with regards to the process of change, the use of video enhanced reflection and the nature of conversation in professional development.
A comparison of New European fire standards with UK standards and the impact on UK vehicle design
Authors: Tooley D
Published: June 2011

The Rail Industry will soon be entering a new phase of rail vehicle design for fire safety as a result of the introduction of new European standards (EN) and requirements in technical specification for interoperability (TSI), which will replace national standards, such as British standards (BS) and Railway Standards and Safety Board group standards. The new standards and specifications are prEN45545, fire protection on railway vehicles, prEN50553, requirements for running capability in case of fire on board rolling stock, safety in railway tunnels TSI, high-speed rolling stock TSI, and conventional rail TSI. The standard and specification changes have a big potential impact in fire safety management of vehicles in the United Kingdom. This article describes changes identified to date, examines their impact on passenger vehicle design and validation requirements, and identifies further work requirements by: (a) giving an overview of current fire safety requirements; (b) describing in some detail the fire safety requirements described in the new standards, including categorization, materials fire performance test methods and requirements, fire resistance requirements, design requirements, fire detection and suppression requirements, requirements for transport of flammable liquids, and requirements for running capability in the event of a fire; (c) discussion on changes in approach which are required as a result of working to the new standards, and changes in vehicle design that may be necessary; (d) work still in progress required to allow close out of current issues. The article concludes that since materials fire performance requirements have not yet been fully investigated, no comment can be yet made concerning whether the performance of trains based on new standards is expected to be equivalent to trains built to current fire safety standards.
Inside the Opponent’s Head
Authors: Saguy Tamar , Kteily Nour
Published: June 2011

Members of groups in conflict typically perceive the same reality in opposing ways. We investigated individuals’ ability to accurately perceive out-group members’ views of the conflict. Drawing on research on power and metaperceptions, we hypothesized that perceiving losses to in-group position would increase accuracy in predicting out-group members’ views. Study 1 was conducted immediately following the Gaza flotilla incident. Israelis, who perceived the event as causing political losses to their group, were more accurate in predicting out-group members’ views of the incident than were Palestinians, who perceived the event as causing political gains for their group. Moreover, Israelis’ accuracy increased with their perception of political losses for Israel, whereas Palestinians’ accuracy decreased with their perception of political gains for Palestinians. These effects were particularly pronounced among those participants who were highly identified with their group. Study 2 replicated the relationship between perceived losses and accuracy, and demonstrated that it could not be accounted for by factors such as education, political orientation, or empathy.
Rifaximin for the treatment of acute infectious diarrhea
Authors: Hong Kyoung Sup , Kim Joo Sung
Published: June 2011

Rifaximin is a nonabsorbable rifamycin derivative with an excellent safety profile and a broad spectrum of antimicrobial activity against a variety of enteropathogens causing acute infectious diarrhea. After oral ingestion, its bioavailability is known to be less than 0.4%, and it has a low potential for significant drug interactions. In the treatment of travelers’ diarrhea caused by noninvasive diarrheagenic Escherichia coli, it has been demonstrated that rifaximin significantly shortens the duration of diarrhea and has an efficacy similar to that of ciprofloxacin. Moreover, according to two randomized placebo-controlled trials, prophylactic treatment with rifaximin reduced the risk of developing travelers’ diarrhea by more than 50% compared with the placebo group. For the treatment of acute diarrhea unrelated to travel, a short course of rifaximin significantly reduced the duration of diarrhea, and its overall efficacy was comparable to that of ciprofloxacin. The discrepancy between the in vitro and in vivoantimicrobial activities of rifaximin, however, and the clinical implication of the rapid appearance of bacterial resistance, must be further elucidated. In conclusion, this gut-selective antibiotic seems to be a promising option for the treatment of acute infectious diarrhea secondary to noninvasive E. coli and also appears to be effective in chemoprophylaxis for travelers’ diarrhea.
Is Coming Out Always a “Good Thing”? Exploring the Relations of Autonomy Support, Outness, and Wellness for Lesbian, Gay, and Bisexual Individuals
Authors: Legate Nicole , Ryan Richard M. , Weinstein Netta
Published: June 2011

Prior research suggests that, on average, disclosing sexual identity (being “out”) yields wellness benefits for lesbian, gay, and bisexual (LGB) individuals. LGB individuals vary, however, both in how much they disclose their sexual orientation in different social contexts and in the experiences that follow from disclosure. The present research examines this within-person variation in disclosure and its consequences as a function of the autonomy supportive versus controlling character of social contexts. LGB individuals rated experiences of autonomy support and control in the contexts of family, friends, coworkers, school, and religious community, as well how “out” they were, and their context-specific self-esteem, depression, and anger. Findings from multilevel modeling revealed that LGB individuals were more likely to disclose in autonomy supportive contexts. Additionally, whereas disclosure was associated with more positive well-being in autonomy supportive contexts, in controlling contexts it was not. Practical and research implications are discussed.
An approach for protecting transport infrastructure
Authors: Khoudour L , El-Koursi E M , Velastin S A , Buch N , Lim-Thiebot S , Fontaine F
Published: June 2011

Scientific and technological innovations are often sources of new vulnerabilities, hazards and risks impacting equipment, systems, processes, organization, and human behaviours. The issues of safety, security, performance, and their management in a holistic approach are quickly becoming essential for every industrial sector. This article discusses safety and security policy focused on the protection of critical railway infrastructure. The article suggests a global approach for risk appraisal and threat assessment in the railway sector, and highlights some of the technologies for the monitoring and surveillance of rail linear infrastructures.
Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis
Authors: Kumar Shaji , Zhang Mei-Jie , Li Peigang , Dispenzieri Angela , Milone Gustavo A. , Lonial Sagar , Krishnan Amrita , Maiolino Angelo , Wirk Baldeep , Weiss Brendan , Freytes César O. , Vogl Dan T. , Vesole David H. , Lazarus Hillard M. , Meehan Kenneth R. , Hamadani Mehdi , Lill Michael , Callander Natalie S. , Majhail Navneet S. , Wiernik Peter H. , Nath Rajneesh , Kamble Rammurti T. , Vij Ravi , Kyle Robert A. , Gale Robert Peter , Hari Parameswaran N.
Published: June 2011

Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% > 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P < .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P < .0001).
Cytoskeletal remodeling mediated by WASp in dendritic cells is necessary for normal immune synapse formation and T-cell priming
Authors: Bouma Gerben , Mendoza-Naranjo Ariadna , Blundell Michael P. , de Falco Elena , Parsley Kathryn L. , Burns Siobhan O. , Thrasher Adrian J.
Published: June 2011

Rearrangement of the cytoskeleton in T cells plays a critical role in the organization of a complex signaling interface referred to as immunologic synapse (IS). Surprisingly, the contribution of antigen presenting cells, in particular dendritic cells (DCs), to the structure and function of the IS has not been investigated in as much detail. We have used a natural model of cytoskeletal dysfunction caused by deficiency of the Wiskott-Aldrich syndrome protein (WASp) to explore the contribution of the DC cytoskeleton to IS formation and to T-cell priming. In an antigen-specific system, T-DC contacts were found to be less stable when DCs alone lacked WASp, and associated with multiple defects of IS structure. As a consequence, DCs were unable to support normal IL-12 secretion, and events downstream of TCR signaling were abrogated, including increased calcium flux, microtubule organizing center (MTOC) polarization, phosphorylation of ZAP-70, and T-cell proliferation. Formation of an effective signaling interface is therefore dependent on active cytoskeletal rearrangements in DCs even when T cells are functionally competent. Deficiency of DC-mediated activities may contribute significantly to the varied immunodysregulation observed in patients with WAS, and also in those with limited myeloid reconstitution after allogeneic hematopoietic stem cell transplantation.